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A role for cardiac mast cells in the pathogenesis of hypertensive heart disease
Abstract
Cardiac mast cells participate in myocardial dysfunction, but the mechanisms are presently unknown.
By examining spontaneously hypertensive rats (SHRs) during their entire lifespan, we attempted to define the role of mast cells in the induction of cardiac hypertrophy and transition to heart failure.
By contrast to normotensive littermates, hearts of newborn SHRs already contained mast cells. In the prehypertensive (2-week-old) SHRs, the increased expression of c-kit and soluble stem cell factor correlated with an increased number of cardiac mast cells. The mast cells contained tumour necrosis factor-alpha which, together with nuclear factor kappa-B (NF-kappaB) and interleukin (IL)-6, was significantly induced in the prehypertensive SHRs. Stimulation of cardiac mast cells with compound 48/80 in an ex-vivo Langendorff heart perfusion system resulted in increased expression of nuclear factor Kappa-B (NF-kappaB) (four-fold) and IL-6 (nine-fold) mRNA in the left ventricles of adult rat hearts. In the presence of an inhibitor of mast cell degranulation, disodium cromoglycate, the induced expression of NF-kappaB and IL-6 was inhibited. In the late hypertensive stage, the hearts of SHRs with advanced cardiac hypertrophy (12-month-old) and heart failure (20-month-old) had significantly increased levels of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF), and displayed increased myocardial fibrosis. Activated mast cells were a major source of TGF-beta1 and bFGF, and localized to areas of myocardial fibrosis.
By synthesizing and secreting prohypertrophic cytokines and profibrotic growth factors, cardiac mast cells participate in the induction of cardiac hypertrophy and cardiac fibrosis, which are the key steps in the transition to heart failure.
... Activation of the ɛPKC signaling 7 pathway in mast cells was responsible for mast cell degranulation and subsequent TGF-β release [79]. In line with these findings, in spontaneously hypertensive rats, expression of mast cell-derived TGFβ and bFGF significantly increased during the transition from cardiac hypertrophy to heart failure and was associated with an exaggerated myocardial fibrosis [80]. ...
... Growing evidence suggests that inflammatory mediators released from mast cells are critically involved in the development of pressure overload-induced cardiac remodeling. In spontaneously hypertensive rats, left ventricular nuclear factor kappa-B and IL-6 expression in mast cells were already increased during the prehypertensive stages [80]. Stimulation of cardiac mast cell degranulation with the compound 48/80 in an ex-vivo Langendorff heart preparations resulted in increased expression of nuclear factor kappa-B and IL-6 mRNA in left ventricles [80]. ...
... In spontaneously hypertensive rats, left ventricular nuclear factor kappa-B and IL-6 expression in mast cells were already increased during the prehypertensive stages [80]. Stimulation of cardiac mast cell degranulation with the compound 48/80 in an ex-vivo Langendorff heart preparations resulted in increased expression of nuclear factor kappa-B and IL-6 mRNA in left ventricles [80]. These data are supported by recent findings of single-cell sequencing of immune infiltrates in left ventricles of mice subjected to pressure overload, which revealed that mast cells had the highest expression of IL-6 among all immune cells [39]. ...
In response to various stressors, cardiac chambers undergo structural remodeling. Long-term exposure of the right ventricle (RV) to pressure or volume overload leads to its maladaptive remodeling, associated with RV failure and increased mortality. While left ventricular adverse remodeling is well understood and therapeutic options are available or emerging, RV remodeling remains underexplored and no specific therapies are currently available. Accumulating evidence implicates a role of mast cells in RV remodeling. Mast cells produce and release numerous inflammatory mediators, growth factors and proteases that can adversely affect cardiac cells, thus contributing to cardiac remodeling. Recent experimental findings suggest that mast cells might represent a potential therapeutic target. This review examines the role of mast cells in cardiac remodeling with specific focus on RV remodeling and explores the potential efficacy of therapeutic interventions targeting mast cells to mitigate adverse RV remodeling.
... Mast cells are also present in the normal heart tissues in humans and animals (Marone et al. 2000) and an increasing number of studies suggest possible roles of cardiac mast cells in the pathogenesis of various cardiovascular diseases . In particular, enhanced accumulation of mast cells in hypertensive and failing left ventricles has been documented (Panizo et al. 1995;Shiota et al. 2003;Batlle et al. 2006). Recent studies have identified important roles for mast cells in left ventricular hypertrophy and failure (Hara et al. 2002;Kitaura-Inenaga et al. 2003;Stewart et al. 2003). ...
... In the rat model of left ventricular hypertrophy induced by transverse aortic constriction, the number of cardiac mast cells increased from about 2 cells/mm 2 in sham animals to 3 cells/mm 2 5 weeks post surgery (Li et al. 2016). Comparable cardiac mast cell densities are reported in spontaneously hypertensive rats (Shiota et al. 2003). The temporal responses in the density of myocardial mast cells in the model of biventricular volume overload was similar for the left ventricle and RV . ...
... In contrast, mast cell density started increasing after 2 weeks and reached maximal values 3 weeks post surgery. Interestingly, increased expression of c-Kit and soluble stem cell factor and enhanced cardiac mast cells density were observed in the prehypertensive spontaneously hypertensive rats even before any signs of cardiac hypertrophy or fibrosis (Shiota et al. 2003). An early elevation in mast cell density in both left and right ventricles was observed in a rat model of biventricular volume overload Forman et al. 2006). ...
Right ventricular (RV) remodeling represents a complex set of functional and structural adaptations in response to chronic pressure or volume overload due to various inborn defects or acquired diseases and is an important determinant of patient outcome. However, the underlying molecular mechanisms remain elusive. We investigated the time course of structural and functional changes in the RV in the murine model of pressure overload-induced RV hypertrophy in C57Bl/6J mice. Using magnetic resonance imaging, we assessed the changes of RV structure and function at different time points for a period of 21 days. Pressure overload led to significant dilatation, cellular and chamber hypertrophy, myocardial fibrosis, and functional impairment of the RV. Progressive remodeling of the RV after pulmonary artery banding (PAB) in mice was associated with upregulation of myocardial gene markers of hypertrophy and fibrosis. Furthermore, remodeling of the RV was associated with accumulation and activation of mast cells in the RV tissue of PAB mice. Our data suggest possible involvement of mast cells in the RV remodeling process in response to pressure overload. Mast cells may thus represent an interesting target for the development of new therapeutic approaches directed specifically at the RV.
... Mast cells are derived from precursor cells in the bone marrow and locally mature under the influence of the c-Kit ligand, stem cell factor (SCF), with their final phenotype being dependent on the microenvironment in which they reside. Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy [12,13] and in animal models of experimentally induced hypertension [14][15][16], myocardial infarction [17], and chronic volume overload secondary to aortocaval fistula [11] and mitral regurgitation [18,19]. Furthermore, there is evolving evidence implicating the cardiac mast cell as having a major role in the adverse remodeling underlying these cardiovascular disorders. ...
... As stated earlier, mast cell density is also increased in the hypertensive heart, and, here too, it would appear that SCF is responsible [14]. However, unlike the volume overload condition, the hypertension-related increase does not appear to be the result of mast cell activation. ...
... Here it is assumed that, as a result of sympathectomy, substance P was depleted thereby preventing mast cell activation. While SCF was not measured in these two studies, the results of Shiota et al. [14] would indicate that it would remain elevated despite the prevention of mast cell degranulation and hence result in an increase in mast cell density. ...
Cardiac mast cells store and release a variety of biologically active mediators, several of which have been implicated in the activation of matrix metalloproteinases in the volume-overloaded heart, while others are involved in the fibrotic process in pressure-overloaded hearts. Increased numbers of mast cells have been reported in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic cardiac volume overload. Also, there is evolving evidence implicating the cardiac mast cell as having a major role in the adverse remodeling underlying these cardiovascular disorders. Thus, the cardiac mast cell is the focus of this chapter that begins with a historical background, followed by sections on methods for their isolation and characterization, endogenous secretagogues, phenotype, and ability of estrogen to alter their phenotype so as to provide cardioprotection. Finally the role of mast cells in myocardial remodeling secondary to a sustained cardiac volume overload, hypertension, and ischemic injury and future research directions are discussed.
... Rights reserved. myocardial ischemia [42][43][44], myocardial infarction [45], hypertension [46], and CHF [47]. Specifically, studies show histamine levels are higher in animal hearts suffering from idiopathic and dilated ischemic cardiomyopathies and cardiac mast cells play a physiological role in cardiac hypertrophy and fibrosis, both important processes in the transition to hypertensive heart failure [46,47]. ...
... myocardial ischemia [42][43][44], myocardial infarction [45], hypertension [46], and CHF [47]. Specifically, studies show histamine levels are higher in animal hearts suffering from idiopathic and dilated ischemic cardiomyopathies and cardiac mast cells play a physiological role in cardiac hypertrophy and fibrosis, both important processes in the transition to hypertensive heart failure [46,47]. Both animal and human (post-autopsy and explanted heart) studies have also found an increased number of mast cells in the tunica media of stable and unstable atherosclerotic coronary lesions after myocardial infarction, suggesting that histamine may be involved in the onset of infarction or that infarction triggers intra-plaque infiltration of mast cells, possibly increasing the risk of reinfarction [42][43][44][45]. ...
Purpose
Acid suppressive therapy using histamine H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) can be utilized for the prevention of gastrointestinal bleeding (GIB) among patients with cardiovascular disease receiving dual antiplatelet therapy (DAPT). However, emerging data suggests underlying associations between PPI or H2RA use and cardiovascular disease incidence, progression, and mortality. This review explores the history of acid suppressive therapies and their use in cardiovascular disease patients and the growing evidence in support of H2RA use.
Recent Findings
PPIs were originally championed as better than H2RAs for preventing GIB events in cardiovascular disease patients on DAPT therapy, but there is evidence to suggest that drug-drug interactions between clopidogrel and PPIs may translate to worse cardiovascular outcomes. Studies demonstrating PPI superiority in the setting of DAPT were also limited due to small sample sizes and high levels of bias. Consequently, there is renewed interest in H2RAs for patients on DAPT with some data demonstrating similar or improved clinical outcomes over PPI therapy. Additionally, studies have discovered a possible role for H2RAs in the management of heart failure (HF) incidence, symptoms, and mortality.
Summary
Studies comparing H2RAs and PPIs in patients on DAPT have demonstrated mixed results for cardiovascular and GIB outcomes, with several studies being underpowered and limited by biases. Recent clinical and pre-clinical studies now support the noninferiority of H2RAs for major outcomes and even utility in HF. These findings suggest that H2RAs may warrant reconsideration as an acid suppressive therapy over PPIs for patients on DAPT or with HF.
... As previously mentioned, there is a small population of resident mast cells that plays an important role in homeostasis in the normal myocardium and during pathological events. Expansion of the mast cell population is associated with cardiac fibrosis in response to multiple pathological challenges (Frangogiannis et al., 1998b;Patella et al., 1998;Shiota et al., 2003;Wei et al., 2003). The mechanisms associated with this expansion is not well understood. ...
... Mast cells are known to have abundant numbers of granules that store a wide range of mediators. This includes many profibrotic mediators including TNF-α (Frangogiannis et al., 1998a), TGF-β (Shiota et al., 2003), and platelet-derived growth factor (PDGF) (Nazari et al., 2016). However, these mediators are produced by many cell types and the relative contribution of mast cells has not been fully elucidated. ...
Heart failure is a leading cause of death worldwide. While there are multiple etiologies contributing to the development of heart failure, all cause result in impairments in cardiac function that is characterized by changes in cardiac remodeling and compliance. Fibrosis is associated with nearly all forms of heart failure and is an important contributor to disease pathogenesis. Inflammation also plays a critical role in the heart and there is a large degree of interconnectedness between the inflammatory and fibrotic response. This review discusses the cellular and molecular mechanisms contributing to inflammation and fibrosis and the interplay between the two.
... A significant increase in mast cell density and extent of hypertrophy and failure has been observed in the heart [94]. ...
... Evidence indicates that constitutive expression of TNF-α is additionally localized in cardiac mast cells. Mast cell stimulation activates TNF-α /NF-κ B /IL-6 cascades to induce cardiac hypertrophy [94]. TNF-α induces the activation of p38 MAPK, which further activates NF-κ B and hypertrophic genes to cause cardiac hypertrophy and dysfunction of heart [105,106]. ...
Cardiac hypertrophy, which occurs due to chronic haemodynamic overload, is one of the numerous biological adaptations to environmental requirements. The adaptation represents the sum of various modifications in gene expression. It is now apparent that hypertrophy of overloaded heart is a complex process, that is both beneficial to compensate the overload, and detrimental because the hypertrophied cells are not normal. There are some conditions in which cardiac hypertrophy are observed such as hypertension, diabetes, obesity, atherosclerosis and many others. Signaling mechanisms involved in the progression of cardiac hypertrophy are Calcineurin/NFAT, Cyclic GMP/PKG-1, PI3K/AKT/GSK-3, GPCRs, Small G-proteins, MAPK, GP130/STAT signaling, Renin-angiotensin system, Atrial natriuretic factor, Nitric oxide, TNF-α, Oxidant signaling and Endothelins. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway plays a role in cardiac pathophysiology.
... Chymase and tryptase in association with other mediators (e.g., cytokines, TNFα, chemokines, leukotrienes, transforming growth factor, histamine) promote tissue repair (Douaiher et al., 2014). Cardiac MCs have been found to be involved also in different pathophysiological processes of the myocardium, including ventricular remodeling, that is, alterations in size, shape, structure, and function of the heart caused by MI (through atherosclerotic lesions or coronary vasospasm), volume overload, chronic hypertension or myocarditis (Gilles et al., 2003;Higuchi et al., 2008;Huang et al., 2013;Levick et al., 2011;Melendez et al., 2011;Palaniyandi et al., 2008), arrhythmias (Koda et al., 2010;Mackins et al., 2006;Morrey et al., 2010), graft rejection following cardiac transplantation (Li et al., 1992;Zweifel et al., 2002), dilated cardiomyopathy (Selvaraj et al., 2005), cardiac hypertrophy, heart failure (Balakumar et al., 2008;Batlle et al., 2006;Hara et al., 2002;Joseph et al., 2003;Kim et al., 2006;Shiota et al., 2003), Takotsubo cardiomyopathy (Cheng & Kounis, 2012;Vultaggio et al., 2007). Moreover, MCs within the arterial walls are involved in the progression of atherosclerosis in epicardial coronary arteries, in carotid arteries (Jeziorska et al., 1997;Lehtonen-Smeds et al., 2005;Willems et al., 2013) and in the aorta (Ramalho et al., 2013) and its clinical complications, such as the ACSs (Deliargyris et al., 2005;Forman et al., 1985;Kaartinen et al., 1998;Kervinen et al., 2005;Steffel et al., 2005), and in the development of AAA (Wang & Shi, 2012;Zhang et al., 2011). ...
... Though supported by animal experiments (Balakumar et al., 2008;Batlle et al., 2006;Hara et al. 2002;Joseph et al. 2003;Kim et al., 2006;Shiota et al., 2003), the involvement of MCs in the development of congestive heart failure in humans is unclear (Clarke, 2012;McElroy et al., 1998;Sotlar et al., 1997). In a retrospective cohort study including 548 Danish adults with mastocytosis, patients presented with congestive heart failure (2%), perivascular disease (2%), and MI (2%) (Cohen et al., 2014). ...
Mast cells are tissue-resident cells, which have been proposed to participate in various inflammatory diseases, among them the cardiovascular diseases (CVDs). For mast cells to be able to contribute to an inflammatory process, they need to be activated to exocytose their cytoplasmic secretory granules. The granules contain a vast array of highly bioactive effector molecules, the neutral protease tryptase being the most abundant protein among them. The released tryptase may act locally in the inflamed cardiac or vascular tissue, so contributing directly to the pathogenesis of CVDs. Moreover, a fraction of the released tryptase reaches the systemic circulation, thereby serving as a biomarker of mast cell activation. Actually, increased levels of circulating tryptase have been found to associate with CVDs. Here we review the biological relevance of the circulating tryptase as a biomarker of mast cell activity in CVDs, with special emphasis on the relationship between activation of mast cells in their tissue microenvironments and the pathophysiological pathways of CVDs. Based on the available in vitro and in vivo studies, we highlight the potential molecular mechanisms by which tryptase may contribute to the pathogenesis of CVDs. Finally, the synthetic and natural inhibitors of tryptase are reviewed for their potential utility as therapeutic agents in CVDs.
... Chronic heart failure. Despite the evidence for a role of MCs in the evolution of congestive heart failure obtained in animal models [35][36][37][38][39][40] case reports of heart failure in SM patients are scarce. [108][109][110] In a Danish retrospective cohort study of 548 adults with SM only 12 patients had a congestive heart failure. ...
... These alterations are probably due to the remodeling effect of prohypertrophic cytokines and proteases and profibrotic growth factors synthesized and secreted by MCs. 27,37,114,115 Therapeutic options. The medical treatment options of patients with chronic heart failure (New York Heart Association class II-IV) based on the European guidelines 116 are also valid for MCAD patients with clinically manifest heart failure. ...
Traditionally, mast cell activation disease (MCAD) has been considered as just one rare (neoplastic) disease, mastocytosis, focused on the mast cell (MC) mediators tryptase and histamine and the suggestive, blatant symptoms of flushing and anaphylaxis. Recently another form of MCAD, the MC activation syndrome, has been recognized featuring inappropriate MC activation with little to no neoplasia and likely much more heterogeneously clonal and far more prevalent than mastocytosis. Increasing expertise and appreciation has been established for the truly very large menagerie of MC mediators and their complex patterns of release, engendering complex, nebulous presentations of chronic and acute illness best characterized as multisystem polymorbidity of generally inflammatory ± allergic theme. We describe the pathogenesis of MCAD with a particular focus on clinical cardiovascular symptoms and the therapeutic options for MC mediator-induced cardiovascular symptoms.
... CatS appears to be involved in the development of various pathological conditions such as cardiovascular disease, obesity, and inflammatory diseases [19]. CatG is known to be a serine protease released from neutrophils [10] and MCs associated with inflammatory processes [28][29][30][31] and HF progression [31][32][33]. CatG concentration and activity were reported to decrease along with the reduction of inflammation and MC proinflammatory-type concentration [28]. ...
... CatS appears to be involved in the development of various pathological conditions such as cardiovascular disease, obesity, and inflammatory diseases [19]. CatG is known to be a serine protease released from neutrophils [10] and MCs associated with inflammatory processes [28][29][30][31] and HF progression [31][32][33]. CatG concentration and activity were reported to decrease along with the reduction of inflammation and MC proinflammatory-type concentration [28]. After LVAD support, inflammatory cytokines remained significantly high [17,20,34] and the existence of a relationship between inflammatory cytokines and cathepsins has been shown in HF [5]. ...
Background
In end-stage heart failure (HF), the implantation of a left ventricular assist device (LVAD) is able to induce reverse remodeling. Cellular proteases, such as cathepsins, are involved in the progression of HF. The aim of this study was to evaluate the role of cathepsin system in HF patients supported by LVAD, in order to determine their involvement in cardiac remodeling.Methods
The expression of cysteine (CatB, CatK, CatL, CatS) and serine cathepsin (CatG), and relative inhibitors (Cystatin B, C and SerpinA3, respectively) was determined in cardiac biopsies of 22 patients submitted to LVAD (pre-LVAD) and compared with: 1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior LVAD (HT, n¿=¿7); 2) patients supported by LVAD at the moment of transplantation (post-LVAD, n¿=¿6).ResultsThe expression of cathepsins and their inhibitors was significantly higher in pre-LVAD compared to the HT group and LVAD induced a further increase in the cathepsin system. Significant positive correlations were observed between cardiac expression of cathepsins and their inhibitors as well as inflammatory cytokines. In the pre-LVAD group, a relationship of cathepsins with dilatative etiology and length of hospitalization was found.ConclusionsA parallel activation of cathepsins and their inhibitors was observed after LVAD support. The possible clinical importance of these modifications is confirmed by their relation with patients¿ outcome. A better discovery of these pathways could add more insights into the cardiac remodeling during HF.
... We also observed an augmentation of chymase mRNA levels in cardiac tissues in the placebo group. Previously, Shiota et al. [48] reported that chymase mRNA levels in cardiac tissues were significantly augmented in SHRs compared with WKY rats. They also observed the up-regulation of mRNA levels of TNF-a, collagen I and collagen III in cardiac tissues in SHRs [48]. ...
... Previously, Shiota et al. [48] reported that chymase mRNA levels in cardiac tissues were significantly augmented in SHRs compared with WKY rats. They also observed the up-regulation of mRNA levels of TNF-a, collagen I and collagen III in cardiac tissues in SHRs [48]. However, the relationship between the augmentation of cardiac chymase mRNA levels and cardiac remodeling in SHRs is not clear. ...
Objective: To clarify the role of chymase in hypertension, we evaluated the effect of a chymase inhibitor, TY-51469, on vascular dysfunction and survival in stroke-prone spontaneously hypertensive rats (SHR-SP).
Methods: SHR-SP were treated with TY-51469 (1 mg/kg per day) or placebo from 4 to 12 weeks old or until death. Wistar-Kyoto rats were used as a normal group.
Results: SBP was significantly higher in both the placebo and TY-51469 groups than in the normal group, but there was no significant difference between the two treatment groups. Plasma renin, angiotensin-converting enzyme activity and angiotensin II levels were not different between the placebo and TY-51469 groups. In contrast, vascular chymase-like activity was significantly higher in the placebo than in the normal group, but it was reduced by TY-51469. Acetylcholine-induced vascular relaxation was significantly higher in the TY-51469 group than in the placebo group. There was significant augmentation of the number of monocytes/macrophages and matrix metalloproteinase-9 activity in aortic tissue from the placebo group compared with the normal group, and these changes were attenuated by TY-51469. There were also significant increases in mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-[alpha] in the placebo group that were attenuated by TY-51469. Cumulative survival was significantly prolonged in the TY-51469 group compared with the placebo group.
Conclusion: Chymase might play an important role in vascular dysfunction via augmentation both of matrix metalloproteinase-9 activity and monocyte/macrophage accumulation in SHR-SP, and its inhibition may be useful for preventing vascular remodeling and prolonging survival.
... Mast cells and eosinophils are mostly known for their involvement in allergic diseases. While consistent evidence points to mast cells' contribution to the pathogenesis of hypertensive heart disease [89,90], cardiac eosinophils protect against cardiac fibrosis and hypertrophy [91] (Fig. 2). How these cells can interfere with cardiac MMP-2 is still speculative, although some mechanisms were described for allergic conditions. ...
Hypertension is one of the leading risk factors for the development of heart failure. Despite being a multifactorial disease, in recent years, preclinical and clinical studies suggest strong evidence of the pivotal role of inflammatory cells and cytokines in the remodeling process and cardiac dysfunction. During the heart remodeling, activation of extracellular matrix metalloproteinases (MMPs) occurs, with MMP-2 being one of the main proteases secreted by cardiomyocytes, fibroblasts, endothelial and inflammatory cells in cardiac tissue. In this review, we will address the process of cardiac remodeling and injury induced by the increase in MMP-2 and the main signaling pathways involving cytokines and inflammatory cells in the process of transcriptional, secretion and activation of MMP-2. In addition, an interaction and coordinated action between MMP-2 and inflammation are explored and significant in maintaining the cardiac cycle. These observations suggest that new therapeutic opportunities targeting MMP-2 could be used to reduce inflammatory biomarkers and reduce cardiac damage in hypertension.
... Mature myocardium also contains a small number of mast cells. Mast cells are stimulated by complement, reactive oxygen species, adenosine or cytokines to degranulate and release mediators that promote the activation of fibroblasts, such as TNF-α (Frangogiannis et al., 1998a), TGF-β (Shiota et al., 2003), IL-4 (Kanellakis et al., 2012) and platelet-derived growth factor (PDGF) (Nazari et al., 2016). Moreover, mast cells produce two specific proteases: tryptase and chymotrypsin (de Almeida et al., 2002). ...
Cardiovascular disease is a group of diseases with high mortality in clinic, including hypertension, coronary heart disease, cardiomyopathy, heart valve disease, heart failure, to name a few. In the development of cardiovascular diseases, pathological cardiac remodeling is the most common cardiac pathological change, which often becomes a domino to accelerate the deterioration of the disease. Therefore, inhibiting pathological cardiac remodeling may delay the occurrence and development of cardiovascular diseases and provide patients with greater long-term benefits. Resveratrol is a non-flavonoid polyphenol compound. It mainly exists in grapes, berries, peanuts and red wine, and has cardiovascular protective effects, such as anti-oxidation, inhibiting inflammatory reaction, antithrombotic, dilating blood vessels, inhibiting apoptosis and delaying atherosclerosis. At present, the research of resveratrol has made rich progress. This review aims to summarize the possible mechanism of resveratrol against pathological cardiac remodeling, in order to provide some help for the in-depth exploration of the mechanism of inhibiting pathological cardiac remodeling and the development and research of drug targets.
... 5 However, this histamine receptor subtype also abundantly expresses in cardiovascular system and mediates histamine-induced positive chronotropic and inotropic effects in cardiomyocytes and vasodilatory effects in vascular endothelial cells. [6][7][8] Since H2R was closely associated with the development of many cardiovascular diseases, such as hypertension, 9 myocardial infarction, 10 and HF, 11 H2RAs might serve as a new potential treatment for various cardiovascular diseases. As for HF, the clinical practice of this kind of treatment has been paid intensive attention to during the last decades. ...
Aims
Previous studies reported that histamine H2 receptor antagonists (H2RAs) had cardioprotective effects. However, the effect of H2RAs on mortality of critical ill patients with heart failure (HF) remains unclear. The aim of this study was to clarify the association between H2RAs and all-cause mortality of critical ill patients with HF based on Medical Information Mart for Intensive Care III database (MIMIC-III).
Methods and results
Propensity score matching (PSM) was applied to account for the baseline differences between two groups that were exposed to H2RAs or not. The study primary outcome was all-cause mortality. Kaplan–Meier curves and multivariable Cox regression models were employed to estimate the effects of H2RAs on mortality of critical ill patients with HF. A total of 10 387 patients were included, involving 4440 H2RAs users and 5947 non-H2RAs users. After matching, 3130 pairs of patients were matched between H2RAs users and non-H2RAs users. The results showed significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortality in both univariate analyses and multivariate analyses [hazard ratio (HR) = 0.73, 95% confidence interval (CI): 0.65–0.83 for 30-day; HR = 0.80, 95%CI: 0.72–0.89 for 90-day; and HR = 0.83, 95%CI: 0.76–0.90 for 1-year mortality, respectively] by Cox regression after PSM. Furthermore, stratified analyses revealed that the 30-day, 90-day, and 1-year mortality of ranitidine users were significantly lower than those of famotidine users, respectively.
Conclusion
Histamine H2 receptor antagonists exposure was associated with lower mortality in critical ill patients with HF. Furthermore, ranitidine might be superior to famotidine in reducing mortality of critical ill patients with HF.
... сердце, в силу своих тесных взаимосвязей с эндокринной, нервной и иммунной атеросклерозе и экспериментальной патологии миокарда[10][11][12]. Высказывается предположение, что ТК через активацию фибробластов осуществляют замещение некротизированных клеток миокарда соединительной тканью. ...
... MC granules contain bFGF and IL1β that may also promote cardiomyocyte enlargement and remodeling after MC activation by IgE in vivo or in vitro (Figure 2). MCs are the major source of cardiac bFGF (Shiota et al., 2003). While the 18-kDa bFGF acts in adaptive trophic response, the 34-kDa high-molecular-weight bFGF exacerbates hypertrophy and contributes to cardiac cell death, thereby driving the myocardium towards a maladaptive phenotype (Kardami et al., 2004). ...
Pressure overload and heart failure are among the leading causes of cardiovascular morbidity and mortality. Accumulating evidence suggests that inflammatory cell activation and release of inflammatory mediators are of vital importance during the pathogenesis of these cardiac diseases. Yet, the roles of innate immune cells and subsequent inflammatory events in these processes remain poorly understood. Here, we outline the possible underlying mechanisms of innate immune cell participation, including mast cells, macrophages, monocytes, neutrophils, dendritic cells, eosinophils, and natural killer T cells in these pathological processes. Although these cells accumulate in the atrium or ventricles at different time points after pressure overload, their cardioprotective or cardiodestructive activities differ from each other. Among them, mast cells, neutrophils, and dendritic cells exert detrimental function in experimental models, whereas eosinophils and natural killer T cells display cardioprotective activities. Depending on their subsets, macrophages and monocytes may exacerbate cardiodysfunction or negatively regulate cardiac hypertrophy and remodeling. Pressure overload stimulates the secretion of cytokines, chemokines, and growth factors from innate immune cells and even resident cardiomyocytes that together assist innate immune cell infiltration into injured heart. These infiltrates are involved in pro-hypertrophic events and cardiac fibroblast activation. Immune regulation of cardiac innate immune cells becomes a promising therapeutic approach in experimental cardiac disease treatment, highlighting the significance of their clinical evaluation in humans.
... Of note, increasing evidences showed that inflammation was involved in the pathophysiological process of heart remodeling during cardiac hypertrophy. Overexpression of TNF-α induced cardiac hypertrophy and re-expression of fetal gene program [76,77]. It has also been confirmed that TNF-α promoted the abundance of IL-1 and IL-6 which further stimulate hypertrophy growth response [78]. ...
Harmine is a β-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.
... En isolant les mastocytes chez ces patients, une équipe a démontré qu'ils étaient plus sensibles à une activation par les IgE et le SCF, avec des taux d'histamine, tryptase et LTC4 beaucoup plus élevés que chez les mastocytes isolés de contrôles(Patella et al., 1997). Ce phénotype contribue à les impliquer dans le développement des cardiomyopathies.Les mastocytes semblent également jouer un rôle dans l'insuffisance cardiaque puisque chez des rats hypertendus spontanément et développant de l'insuffisance cardiaque, il a été retrouvé des mastocytes précocement et proche des zones de fibroses cardiaque(Shiota et al., 2003). Une étude a également étudié des souris déficientes en mastocytes et des contrôles soumises à une ligature partielle de l'aorte abdominale. ...
L’insuffisance cardiaque engendre un décès toutes les 7 minutes en France. Cependant, il n’existe aucun traitement pour l’insuffisance cardiaque à fraction d’éjection préservée (ICFEp) qui représente aujourd’hui 50% des cas d’insuffisance cardiaque et dont la prévalence augmente constamment avec le vieillissement de la population. Mieux comprendre l’étiologie et la physiopathologie de cette maladie est primordial pour découvrir des thérapies efficaces pour la prise en charge de cette maladie. L’objectif de cette thèse est d’explorer le rôle de la maladie des petits vaisseaux dans la physiopathologie de l’ICFEp. Plus précisément, nous nous sommes attachés (1) à mieux caractériser le phénotype des capillaires cardiaques chez des souris présentant une dysfonction diastolique, (2) à caractériser les conséquences d’une dysfonction endothéliale sur la structure et la fonction cardiaque et (3) à mieux appréhender les mécanismes moléculaires impliqués dans la régulation de l’intégrité endothéliale par la voie de signalisation Hedgehog (Hh).Nous avons démontré pour la première fois dans un modèle physiopathologique d’ICFEp que les mastocytes sont des acteurs cruciaux du développement de la maladie des microvaisseaux et de la dysfonction diastolique. Nous avons également établi qu’une dysfonction endothéliale caractérisée principalement par une augmentation de la perméabilité vasculaire peut induire une dysfonction diastolique en absence de tout autre facteur de risque cardiovasculaire. En outre, nous avons démontré que le ligand Desert Hedgehog maintient l’intégrité vasculaire en régulant la dégradation de la métalloprotéinase Adam17 dans les cellules endothéliales.L’ensemble de ces résultats démontrent le rôle crucial de la dysfonction endothéliale dans la physiopathologie de l’ICFEp, ainsi que le rôle majeur de Dhh et de la voie de signalisation Hh dans l’intégrité vasculaire notamment dans le cœur.
... This observation indicates that in the heart of normotensive (WKY) and pre-hypertensive (SHR7) rats chymase substantially contributes to local ANG II synthesis. This agrees well with the report on accumulation in the heart of young SHR of mast cells, the source of chymase, the phenomenon that has been demonstrated already in the second week of the animals' life (29). In agreement with our results, chymase inhibition was reported earlier to significantly decrease ANG II generation in the heart (30). ...
Background: Chymase generates angiotensin II (ANG II) independently of angiotensin-converting enzyme in tissues and it contributes to vascular remodeling and development of hypertension, however the exact mechanism of its action is unclear. Methods: Hence, the effects of chymase inhibition were examined in anesthetized spontaneously hypertensive rats (SHR) in two stages of the disease development, ie. pre-hypertensive (SHR7) and with established hypertension (SHR16). Chymostatin, a commercial chymase inhibitor, was infused intravenously alone or in subsequent groups co-infused with captopril. Results: Mean blood pressure (MBP), total renal blood flow (RBF) and ANG II content (plasma and tissues) were measured. In SHR16 chymase blockade significantly decreased MBP (−6%) and plasma (−38%), kidney (−71%) and heart (−52%) ANG II levels. In SHR7 chymostatin did not influence MBP or RBF, but significantly decreased heart ANG II level. Conclusion: Jointly, functional studies and ANG II determinations support the evidence that in SHR chymase can raise plasma ANG II and contribute to blood pressure elevation. We propose that addition of chymase blockade to ACE inhibition could be a promising approach in the treatment of hypertensive patients resistant to therapy with ACE-inhibitors alone.
... The underlying mechanisms of this clinical phenomenon may depend on the tissue where the mast cells are residing and/or the duration of mast cell activation. For example, most of the hypertensive animal models have investigated mast cells in deleterious cardiac remodeling (112,113,159,160,189) and renal mast cells contribute to the pathogenesis of hypertensive nephropathy (224). On the other hand, intravenous infusion of short cell-penetrating peptides, penetratin, and transportan, cause a significant, albeit transient, decrease in BP and this was blocked by a mast cell stabilizing agent (18). ...
Uncontrolled immune system activation amplifies end-organ injury in hypertension. Nonetheless, the exact mechanisms initiating this exacerbated inflammatory response, thereby contributing to further increases in blood pressure (BP), are still being revealed. While participation of lymphoid-derived immune cells has been well described in the hypertension literature, the mechanisms by which myeloid-derived innate immune cells contribute to T cell activation, and subsequent BP elevation, remains an active area of investigation. In this article, we critically analyze the literature to understand how monocytes, macrophages, dendritic cells, and polymorphonuclear leukocytes, including mast cells, eosinophils, basophils, and neutrophils, contribute to hypertension and hypertension-associated end-organ injury. The most abundant leukocytes, neutrophils, are indisputably increased in hypertension. However, it is unknown how (and why) they switch from critical first responders of the innate immune system, and homeostatic regulators of BP, to tissue-damaging, pro-hypertensive mediators. We propose that myeloperoxidase-derived pro-oxidants, neutrophil elastase, neutrophil extracellular traps (NETs), and interactions with other innate and adaptive immune cells are novel mechanisms that could contribute to the inflammatory cascade in hypertension. We further posit that the gut microbiota serves as a set point for neutropoiesis and their function. Finally, given that hypertension appears to be a key risk factor for morbidity and mortality in COVID-19 patients, we put forth evidence that neutrophils and NETs cause cardiovascular injury post-coronavirus infection, and thus may be proposed as an intriguing therapeutic target for high-risk individuals. © 2021 American Physiological Society. Compr Physiol 11:1575-1589, 2021.
... Strengthening this relationship were other studies reporting high numbers of MCs in areas with collagen deposition, in close proximity to the remodeling myocardium as described in explanted human hearts with dilated cardiomyopathy and in animal models of experimentally induced hypertension, myocardial infarction, and chronic cardiac volume overload [201][202][203][204][205][206][207] (Figure 5A). Accordingly, MCs deficient mice models showed reduced inflammatory responses and myocardial damage following a local insult [208]. ...
Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in “sterile” inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis.
... Upon activation, mast cells can degranulate to release stores of preformed mediators, or secrete a variety of compounds de novo with or without degranulation [7]. After myocardial injury, mast cell density is increased in animal models [8,9]. However, the exact role of mast cells in the pathogenesis of myocardial fibrosis is not well understood. ...
Fibrotic remodelling of the atria is poorly understood and can be regulated by myocardial immune cell populations after injury. Mast cells are resident immune sentinel cells present in the heart that respond to tissue damage and have been linked to fibrosis in other settings. The role of cardiac mast cells in fibrotic remodelling in response to human myocardial injury is controversial. In this study, we sought to determine the association between mast cells, atrial fibrosis, and outcomes in a heterogeneous population of cardiac surgical patients, including a substantial proportion of coronary artery bypass grafting patients. Atrial appendage from patients was assessed for collagen and mast cell density by histology and by droplet digital polymerase chain reaction (ddPCR) for mast cell associated transcripts. Clinical variables and outcomes were also followed. Mast cells were detected in human atrial tissue at varying densities. Histological and ddPCR assessment of mast cells in atrial tissue were closely correlated. Patients with high mast cell density had less fibrosis and lower severity of heart failure classification or incidence mortality than patients with low mast cell content. Analysis of a homogeneous population of coronary artery bypass graft patients yielded similar observations. Therefore, evidence from this study suggests that increased atrial mast cell populations are associated with decreased clinical cardiac fibrotic remodelling and improved outcomes, in cardiac surgery patients.
... 6---8 Studies have shown that chronic LV overload increases the density of cardiac mast cells, which when activated release a range of potent inflammatory and pro-fibrotic mediators that play an active part in cardiac remodeling. 9,10 The mechanisms underlying progression of collagen deposition and fibrosis as a result of the presence of cardiac mast cells have not been fully elucidated. Therefore, the purpose of this study was to assess the formation of collagen fibers and mast cell density in hypertensive heart disease, in order to improve our understanding of the pathological processes involved. ...
Objective
To analyze the percentage of collagen fibers and mast cell density in the left ventricular myocardium of autopsied patients with and without hypertensive heart disease.
Methods
Thirty fragments of left ventricular myocardium were obtained from individuals autopsied at the Clinical Hospital of the Federal University of Triângulo Mineiro (UFTM) in the period from 1987 to 2017. Individuals were divided into two groups: those with hypertensive heart disease (HD) and those with no heart disease (ND). Subjects were also assessed according to age, gender and race (white and non-white). Collagen fibers were quantified by computed morphometry and mast cell density was assessed by immunohistochemical methods.
Results
There were significantly more collagen fibers in the left ventricle in the HD group than in the ND group (p< 0.001). Mast cell density was significantly higher in the left ventricle of individuals with HD immunolabeled with anti-chymase and anti-tryptase antibodies (p=0.02) and also of those immunolabeled only with anti-tryptase antibodies (p=0.03). Analyzing the HD group, there was a significant positive correlation between the percentage of collagen fibers in the left ventricle and mast cell density immunolabeled by anti-chymase and anti-tryptase antibodies (p=0.04) and also mast cell density immunolabeled only with anti-tryptase antibodies (p=0.02).
Conclusions
Mast cells are involved in the development of hypertensive heart disease, contributing to the remodeling of collagen fibers in this disease.
... Injury triggers additional MC precursors to infiltrate the myocardium (Ngkelo et al., 2016). For instance, numerous reports have shown increased mast cell counts in DCM patient hearts and animal models of cardiac injury like hypertension and MI (Sperr et al., 1994;Engels et al., 1995;Patella et al., 1997;Shiota et al., 2003;Janicki et al., 2015). This increase in mast cells following injury has led many researchers to question their involvement in cardiac fibrotic remodeling. ...
Cardiac fibrosis begins as an intrinsic response to injury or ageing that functions to preserve the tissue from further damage. Fibrosis results from activated cardiac myofibroblasts, which secrete extracellular matrix (ECM) proteins in an effort to replace damaged tissue; however, excessive ECM deposition leads to pathological fibrotic remodeling. At this extent, fibrosis gravely disturbs myocardial compliance, and ultimately leads to adverse outcomes like heart failure with heightened mortality. As such, understanding the complexity behind fibrotic remodeling has been a focal point of cardiac research in recent years. Resident cardiac fibroblasts and activated myofibroblasts have been proven integral to the fibrotic response; however, several findings point to additional cell types that may contribute to the development of pathological fibrosis. For one, leukocytes expand in number after injury and exhibit high plasticity, thus their distinct role(s) in cardiac fibrosis is an ongoing and controversial field of study. This review summarizes current findings, focusing on both direct and indirect leukocyte-mediated mechanisms of fibrosis, which may provide novel targeted strategies against fibrotic remodeling.
... 6---8 Studies have shown that chronic LV overload increases the density of cardiac mast cells, which when activated release a range of potent inflammatory and pro-fibrotic mediators that play an active part in cardiac remodeling. 9,10 The mechanisms underlying progression of collagen deposition and fibrosis as a result of the presence of cardiac mast cells have not been fully elucidated. Therefore, the purpose of this study was to assess the formation of collagen fibers and mast cell density in hypertensive heart disease, in order to improve our understanding of the pathological processes involved. ...
Objective
To analyze the percentage of collagen fibers and mast cell density in the left ventricular myocardium of autopsied patients with and without hypertensive heart disease.
Methods
Thirty fragments of left ventricular myocardium were obtained from individuals autopsied at the Clinical Hospital of the Federal University of Triângulo Mineiro (UFTM) in the period from 1987 to 2017. Individuals were divided into two groups: those with hypertensive heart disease (HD) and those with no heart disease (ND). Subjects were also assessed according to age, gender and race (white and non-white). Collagen fibers were quantified by computed morphometry and mast cell density was assessed by immunohistochemical methods.
Results
There were significantly more collagen fibers in the left ventricle in the HD group than in the ND group (p< 0.001). Mast cell density was significantly higher in the left ventricle of individuals with HD immunolabeled with anti-chymase and anti-tryptase antibodies (p=0.02) and also of those immunolabeled only with anti-tryptase antibodies (p=0.03). Analyzing the HD group, there was a significant positive correlation between the percentage of collagen fibers in the left ventricle and mast cell density immunolabeled by anti-chymase and anti-tryptase antibodies (p=0.04) and also mast cell density immunolabeled only with anti-tryptase antibodies (p=0.02).
Conclusions
Mast cells are involved in the development of hypertensive heart disease, contributing to the remodeling of collagen fibers in this disease.
... In the human myocardium, mast cells are located in close proximity to cardiomyocytes, coronary microvessels, nerves, and lymphatic vessels [159,[204][205][206][207]. Figure 2 illustrates some of the mediators produced or acting on cardiac mast cells. Unsurprisingly, mast cells and their powerful vasoactive and proinflammatory mediators (e.g., histamine, tryptase, chymase, prostaglandin D2 (PGD2) and cysteinyl leukotriene C4 (LTC4)) were considered to be net detrimental in atherosclerosis [151,[207][208][209][210], myocardial infarction [211,212], myocarditis [213][214][215], dilated cardiomyopaties [159,201], hypertension [216,217] and thrombosis [218]. In the human heart, mast cells are located in the myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. ...
The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct “subpopulations” of mast cells based on a relatively small number of biochemical characteristics. More recently, “subtypes” of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.
... Furthermore, evidence indicates that constitutive expression of TNF-α is in addition localized in cardiac mast cells. Mast cell stimulation activates TNF-α/NF-κβ/IL-6 cascades to induce CH. [52,214] TNF-α also induces the activation of p38 MAPK, which further activates NF-κβ and various hypertrophic genes to cause CH and heart dysfunction. [215] TNF-α and NF-κβ have been shown to be activated in failing hearts of various etiologies, implicating a role of this transcription factor in the pathophysiology of human heart failure. ...
... The presence of mast cells in the LV of SHR has been reported in earlier studies (Janicki et al., 2015;Levick and Widiapradja, 2018;Levick et al., 2011;Ngkelo et al., 2016;Shiota et al., 2003). The role of mast cells in the ailing heart seems to be controversial. ...
... MCs are derived from multipotent hematopoietic bone marrow precursor cells that circulate in the blood and differentiate into mature immunologic cells until reaching the tissue or organ in which they reside. MCs have been found to synthesize transforming growth factor-β1 (TGF-β1) and fibroblast growth factors in cardiac tissues [7]. ...
Introduction: Chymase is primarily found in mast cells (MCs), fibroblasts, and vascular endothelial cells. MC chymase is released into the extracellular interstitium in response to inflammatory signals, tissue injury, and cellular stress. Among many functions, chymase is a major extravascular source for angiotensin II (Ang II) generation. Several recent pre-clinical and a few clinical studies point to the relatively unrecognized fact that chymase inhibition may have significant therapeutic advantages over other treatments in halting progression of cardiac and vascular disease.
Area covered: The present review covers patent literature on chymase inhibitors for the treatment of cardiac diseases registered between 2010 and 2018.
Expert opinion: Increase in cardiac MC number in various cardiac diseases has been found in pathological tissues of human and experimental animals. Meta-analysis data from large clinical trials employing angiotensin converting enzyme (ACE) inhibitors show a relatively small risk reduction of clinical cardiovascular endpoints. The disconnect between the expected benefit associated with Ang II blockade of synthesis or activity underscore a greater participation of chymase compared to ACE in forming Ang II in humans. Emerging literature and a reconsideration of previous studies provide lucid arguments to reconsider chymase as a primary Ang II forming enzyme in human heart and vasculature.
... Despite the presence of RV hypertrophy, mast cell density was not affected in the RV of 3-month-old rats born at high altitude (Rakusan et al., 1990). Mast cells also contribute to cardiac hypertrophy and fibrosis by synthesizing and secreting pro-hypertrophic and pro-fibrotic cytokines (e.g., TNF-α and IL-6) and growth factors [e.g., transforming growth factor (TGF)-β and basic fibroblast growth factor] Shiota et al., 2003;Sun et al., 2007;Meléndez et al., 2010). In addition, mast cells can also promote tissue fibrosis, stimulating proliferation, maturation and synthesis of collagen in cardiac fibroblasts (Liao et al., 2010). ...
Right ventricular (RV) failure is a common consequence of acute and chronic RV overload of pressure, such as after pulmonary embolism and pulmonary hypertension. It has been recently realized that symptomatology and survival of patients with pulmonary hypertension are essentially determined by RV function adaptation to increased afterload. Therefore, improvement of RV function and reversal of RV failure are treatment goals. Currently, the pathophysiology and the pathobiology underlying RV failure remain largely unknown. A better understanding of the pathophysiological processes involved in RV failure is needed, as there is no proven treatment for this disease at the moment. The present review aims to summarize the current understanding of the pathogenesis of RV failure, focusing on inflammation. We attempt to formally emphasize the importance of inflammation and associated representative inflammatory molecules and cells in the primum movens and development of RV failure in humans and in experimental models. We present inflammatory biomarkers and immune mediators involved in RV failure. We focus on inflammatory mediators and cells which seem to correlate with the deterioration of RV function and also explain how all these inflammatory mediators and cells might impact RV function adaptation to increased afterload. Finally, we also discuss the evidence on potential beneficial effects of targeted anti-inflammatory agents in the setting of acute and chronic RV failure.
... Moreover, a growing body of evidence implicates mast cells in various cardiovascular diseases including left ventricular remodeling and failure (Levick et al., 2011). Enhanced accumulation of mast cells in hypertrophied and failing hearts suggests that mast cells play a role in the pathogenesis of these diseases (Panizo et al., 1995;Shiota et al., 2003;Batlle et al., 2006). Studies utilizing mast cell stabilizers, inhibitors of mast cell proteases, and mast cell deficient mice provided further evidence of the importance of mast cells for left ventricular remodeling and failure (Hara et al., 2002;Matsumoto et al., 2003;Levick et al., 2009;Li et al., 2016). ...
Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function.
... Recently, it was found that histamine H2 receptor (H2R) was closely related to the development of various cardiovascular diseases such as myocardial ischemia, [2][3][4] hypertension, [5] myocardial infarction, [6] and CHF as well. [7] Similar to betaadrenergic receptors, H2R is also a Gs-protein coupled receptor and is abundantly expressed in human cardiac myocytes, [8,9] whose activation induces positive chronotropic and inotropic responses [8][9][10][11] and contributes to the exacerbation of myocardial ischemia/reperfusion injury by inducing cardiomyocyte apoptosis. ...
Background:
Histamine H2 antagonists (H2RAs) have long been suggested to have beneficial effects on congestive heart failure (CHF). However, full agreement about the cardioprotective effects of H2RAs is still not reached yet. Therefore, this study aims to clarify the effects of H2RAs on myocardial function in CHF patients by meta-analysis.
Methods:
Electronic databases including PubMed, Embase, and Cochrane Library were retrieved. Randomized controlled trials comparing the cardiac effects of H2RAs and placebo or other medicines were collected. Pooled mean differences (MDs) with 95% confidence intervals (CIs) were calculated and meta-analysis was performed using RevMan 5.3 software.
Results:
A total of 10 studies (472 participants) were included in this meta-analysis. H2RAs exhibited significant negative inotropic and chronotropic effects to reduce heart rate (MD: -3.90; 95%CI: -7.07 to -0.73, P = .02). Furthermore, although H2RAs did not affect the blood pressure in health volunteers, they significantly decreased the blood pressure of CHF patients. Additionally, H2RAs were also associated with significant increase in pre-ejection period and the ratio of pre-ejection period to left ventricular ejection time.
Conclusion:
In summary, these findings showed that H2RAs exerted negative inotropic and chronotropic effects to reduce heart rate and blood pressure, which, similar to beta-adrenergic receptor blockers, might decrease myocardial oxygen demand and eventually result in improvement of CHF symptoms. These data provided further evidence for the effect of H2RAs on cardiac function and novel potential strategy for treatment of CHF.
... Moreover, other reports demonstrate that cardiac chymase contributes to the development of the adverse effects of hypertensive heart failure in rats (15), and that it promotes acute ischemia/reperfusion injury (IRI) in pigs (16). Importantly, in the experimental pig model, inhibition of cardiac mast cell-derived chymase resulted in decreased infarction size after IRI, so making chymase alone responsible for, at least, some of the harmful effects of IRI (16). ...
Apolipoprotein A-I (apoA-I), the main structural and functional protein of HDL particles, is cardioprotective, but also highly sensitive to proteolytic cleavage. Here we investigated the effect of cardiac mast cell activation and ensuing chymase secretion on apoA-I degradation using isolated rat hearts in the Langendorff perfusion system. Cardiac mast cells were activated by injection of compound 48/80 into the coronary circulation or by low-flow myocardial ischemia, after which lipid-free apoA-I was injected, and collected in the coronary effluent for cleavage analysis. Mast cell activation by 48/80 resulted in apoA-I cleavage at sites Tyr192 and Phe229, but hypoxic activation at Tyr192 only. In vitro, the proteolytic end-product of apoA-I with either rat or human chymase was the Tyr192-truncated fragment. This fragment, when compared with intact apoA-I, showed reduced ability to promote migration of cultured human coronary artery endothelial cells in a wound healing assay. We propose that C-terminal truncation of apoA-I by chymase released from cardiac mast cells during ischemia impairs the ability of apoA-I to heal damaged endothelium in the ischemic myocardium.
... Collagen type I and type III are major fibrillar collagens involved in tissue repair (Sun and Weber 1996). An association of TGF-β1 over-expression with cardiac fibrosis has been reported in SHR (Shiota et al. 2003). Some studies showed that TGF-β1 could induce an increased collagen type I and type III synthesis in rats (Lijnen et al. 2000). ...
In the previous study, active extract of Radix Scrophularia (ACRS) demonstrated beneficial effects on ventricular remodeling induced by coronary artery ligation and lowered blood pressure in rats. And ACRS also exhibited the effect on lowering the blood pressure in spontaneously hypertensive rats (SHRs). The aim of this study is to explore the effects of ACRS on ventricular remodeling in SHRs and underlying mechanisms.
ACRS significantly lowered the blood pressure, decreased the heart mass indexes, inhibited the deposition of perivascular and interstitial, attenuated the accumulation of types I and III collagen, reduced the tissue angiotensin II, serum norepinephrine and tumor necrosis factor-α concentrations. The underlying mechanisms may be related to downregulating the mRNA expressions of collagen type I, transforming growth factor-β1 and angiotensin converting enzyme, suppressing the phosphorylation of extracellular signal regulated kinase 1/2, c-Jun N-terminal kinase (JNK/SAPK) and p38 mitogen-activated protein kinases (p38 MAPK).
Continuous treatment of SHRs with ACRS for 21 weeks reduced blood pressure, myocardial hypertrophy and the amount of interstitial and perivascular collagen, which indicated that ACRS could prevent hypertensive ventricular remodeling. This can be attributed to suppression of the sympathetic nervous and renin angiotensin aldosterone system through the inhibition of ERK 1/2, JNK and p38 MAPK pathways.
... Les mastocytes sont localisés à proximité des vaisseaux (Frangogiannis 1999 (Somasundaram 2005). Par ailleurs, les mastocytes sont une source importante de TGFβ, bFGF et VEGF, des facteurs pouvant réguler la croissance des fibroblastes, moduler la matrice extracellulaire et stimuler l'angiogenèse (Shiota 2003). ...
Cardiovascular diseases are the leading cause of mortality worldwide. Coronary events are mainly caused by coronary plaque rupture or erosion. However, at present, there is no noninvasive tool available for the detection of vulnerable plaques. The first part of thesis is about evaluation of new radiotracers for the detection of atherosclerotic vulnerable plaques. 99mTc-B2702p, 20 derivatives, 99mTc-VP and 99mTc-VINP28 were evaluated in an experimental model of atherosclerosis (ApoE-/- mice with left carotid artery ligation). 99mTc- B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques. Myocardial angiogenesis is an important post infarction phenomenon. Angiogenic therapy improves experimentally cardiac parameters. However, clinical trials using the same therapy are more controversial. At present, clinical imaging tools don't allow us to assess angiogenesis therapy. The second part of thesis is about validation of 99mTc-RAFT-RGD in the detection of myocardial angiogenesis. 99mTc-RAFT-RGD allow us to perform noninvasive molecular imaging of myocardial angiogenesis in an experimental model.
... Cardiac mast cell population has strong positive correlation with collagen deposition in hypertrophic heart [47]. It has also been reported that cardiac mast cell density increased dramatically with age in the SHR [48]. In this study, allopurinol treatment prevented the extracellular matrix (ECM) deposition in heart and kidneys of ISO treated rats. ...
We evaluated the preventive effect of allopurinol on isoproterenol (ISO) induced myocardial infarction in aged rats. Twelve-to fourteen-month-old male Long Evans rats were divided into three groups: control, ISO, and ISO + allopurinol. At the end of the study, all rats were sacrificed for blood and organ sample collection to evaluate biochemical parameters and oxidative stress markers analyses. Histopathological examinations were also conducted to assess inflammatory cell infiltration and fibrosis in heart and kidneys. Our investigation revealed that the levels of oxidative stress markers were significantly increased while the level of cellular antioxidants, catalase activity, and glutathione concentration in ISO induced rats decreased. Treatment with allopurinol to ISO induced rats prevented the elevated activities of AST, ALT, and ALP enzymes, and the levels of lipid peroxidation products and increased reduced glutathione concentration. ISO induced rats also showed massive inflammatory cells infiltration and fibrosis in heart and kidneys. Furthermore, allopurinol treatment prevented the inflammatory cells infiltration and fibrosis in ISO induced rats. In conclusion, the results of our study suggest that allopurinol treatment is capable of protecting heart of ISO induced myocardial infarction in rats probably by preventing oxidative stress, inflammation, and fibrosis.
... Chymases are serine proteases released by activated mast cells, involved in tissue repair and inflammatory processes such as wound-healing/fibrosis [1], cardiac remodelling and angiogenesis [2,3]. In humans and rodents, two types of mast cells have been identified. ...
Cardiac fibrosis is a major and complex pathophysiological process that ultimately culminates in cardiac dysfunction and heart failure. This phenomenon includes not only the replacement of the damaged tissue by a fibrotic scar produced by activated fibroblasts/myofibroblasts but also a spatiotemporal alteration of the structural, biochemical, and biomechanical parameters in the ventricular wall, eliciting a reactive remodeling process. Though mechanical stress, post-infarct homeostatic imbalances, and neurohormonal activation are classically attributed to cardiac fibrosis, emerging evidence that supports the roles of immune system modulation, inflammation, and metabolic dysregulation in the initiation and progression of cardiac fibrogenesis has been reported. Adaptive changes, immune cell phenoconversions, and metabolic shifts in the cardiac nonmyocyte population provide initial protection, but persistent altered metabolic demand eventually contributes to adverse remodeling of the heart. Altered energy metabolism, mitochondrial dysfunction, various immune cells, immune mediators, and cross-talks between the immune cells and cardiomyocytes play crucial roles in orchestrating the transdifferentiation of fibroblasts and ensuing fibrotic remodeling of the heart. Manipulation of the metabolic plasticity, fibroblast–myofibroblast transition, and modulation of the immune response may hold promise for favorably modulating the fibrotic response following different cardiovascular pathological processes. Although the immunologic and metabolic perspectives of fibrosis in the heart are being reported in the literature, they lack a comprehensive sketch bridging these two arenas and illustrating the synchrony between them. This review aims to provide a comprehensive overview of the intricate relationship between different cardiac immune cells and metabolic pathways as well as summarizes the current understanding of the involvement of immune–metabolic pathways in cardiac fibrosis and attempts to identify some of the previously unaddressed questions that require further investigation. Moreover, the potential therapeutic strategies and emerging pharmacological interventions, including immune and metabolic modulators, that show promise in preventing or attenuating cardiac fibrosis and restoring cardiac function will be discussed.
The Mast Cells (MCs) are part of the immune system and they are actively involved in the inflammatory and allergic reactions. The MCs produce and release a wide variety of biologically active products, eg, histamine, Tumor necrosis factor-α (TNF-α), Transforming growth factor-β (TGF-β), interleukin and renin, which are involved in cardiac remodelling. MCs are considered culprits in various cardiovascular pathologies such as pressure and volume overload, ventricular dilatation, and heart failure. The deleterious role of MCs in failing heart and myocardial remodelling is being rigorously pursued in animal and human studies. The focus of this mini review is to highlight the detrimental effects of MCs in the cardiac remodelling process
Purpose
: Astronauts in space vehicles beyond low-Earth orbit will be exposed to high charge and energy (HZE) ions, and there is concern about potential adverse effects on the cardiovascular system. Thus far, most animal studies that assess cardiac effects of HZE particles have included only males. This study assessed the effects of oxygen ions (¹⁶O) as a representative ion of the intravehicular radiation environment on the heart of female mice.
Materials and methods
: Female C57BL/6J mice at 6 months of age were exposed to ¹⁶O (600 MeV/n) at 0.25−0.26 Gy/min to a total dose of 0, 0.1, or 0.25 Gy. Cardiac function and abdominal aorta blood velocity were measured with ultrasonography at 3, 5, 7, and 9 months after irradiation. At 2 weeks, 3 months, and 9 months, cardiac tissue was collected to assess collagen deposition and markers of immune cells.
Results
: Ultrasonography revealed increased left ventricle mass, diastolic volume and diameter but there was no change in the abdominal aorta. There was no indication of cardiac fibrosis however, a 75 kDa peptide of left ventricular collagen type III and α-smooth muscle cell actin were increased suggesting some remodeling had occurred. Left ventricular protein levels of the T-cell marker CD2 was significantly increased at all time points, while the neutrophil marker myeloperoxidase was decreased at 2 weeks and 9 months.
Conclusions
: These results taken together suggest ¹⁶O ion exposure did not result in cardiac fibrosis or cardiac dysfunction in female mice. However, it does appear mild cardiac remodeling occurs in response to HZE radiation.
Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are differentiated primarily from resident fibroblasts. Collagen can compensate for the dead cells produced by injury. The appropriate production of collagen is beneficial for preserving the structural integrity of the heart, and protects the heart from cardiac rupture. However, excessive deposition of collagen causes cardiac dysfunction. Recent studies have demonstrated that myofibroblasts can change their phenotypes. In addition, myofibroblasts are found to have functions other than ECM production. Myofibroblasts have macrophage-like functions, in which they engulf dead cells and secrete anti-inflammatory cytokines. Research into fibroblasts has been delayed due to the lack of selective markers for the identification of fibroblasts. In recent years, it has become possible to genetically label fibroblasts and perform sequencing at single-cell levels. Based on new technologies, the origins of fibroblasts and myofibroblasts, time-dependent changes in fibroblast states after injury, and fibroblast heterogeneity have been demonstrated. In this paper, recent advances in fibroblast and myofibroblast research are reviewed.
Mast cells (MCs) play a pivotal role in inflammatory responses and had been studied in inflammatory bone disorders, however, their role in alveolar bone loss induced by periodontal disease (PD) is not yet fully understood. We, therefore, aimed to evaluate the effects of MCs depletion in the PD-induced alveolar bone loss in Wistar (W) and Spontaneously Hypertensive Rats (SHRs). PD was induced by ligating the lower first molars with silk thread one day after the MCs depletion, by the pre-treatment with compound 48/80 for 4 days. After 15 days of PD induction, the hemi-mandibles were surgically collected for qRT-PCR, histological analyses, immunostaining, and ELISA. Systolic blood pressure (SBP) was verified by tail plethysmography to confirm the hypertensive status, and SHR presented SBP >150 mmHg, and previous MC depletion alone or associated with PD did not alter this parameter. SHRs showed a more severe alveolar bone loss compared to W, and MC depletion significantly inhibited this response in both strains, with a more significant response in SHRs. MCs were less abundant in 48/80+PD groups, thus validating the previous MCs depletion in our model. PD increased the number of MC in the gingival tissue of SHR. Cytokine production (TNF-α, IL-6, IL-1β, and CXCL3) was constitutively higher in SHR and increased further after PD, which was also significantly reduced in the MCs-depleted animals. PD led to an increased expression of Opn , Rankl , Rank , Vtn , Itga5 , Itgb5 , Trap , and Ctsk in the mandible of W and SHRs, which was reversed in MCs-depleted animals. These results suggest that MCs significantly contributes to the PD-induced alveolar bone resorption, especially in the SHR, which is associated with a more severe PD progression compared to Wistar, partly explained by these cells contribution to the inflammatory status and mediator production, stimulating osteoclast-related response markers, which were reduced after MC depletion in our experimental model.
Significance:
Fibrosis is a stereotypic, multicellular tissue response to diverse types of injuries that fundamentally result from a failure of cell/tissue regeneration. This complex tissue remodeling response disrupts cellular/matrix composition and homeostatic cell-cell interactions, leading to loss of normal tissue architecture and progressive loss of organ structure/function. Fibrosis is a common feature of chronic diseases that may affect the lung, kidney, liver, and heart.
Recent Advances:
There is emerging evidence to support a combination of genetic, environmental, and age-related risk factors contributing to susceptibility and/or progression of fibrosis in different organ systems. A core pathway in fibrogenesis involving these organs is the induction and activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX) family enzymes.
Critical Issues:
We explore current pharmaceutical approaches to targeting NOX enzymes, including repurposing of currently U.S. Food and Drug Administration (FDA)-approved drugs. Specific inhibitors of various NOX homologs will aid establishing roles of NOXs in the various organ fibroses and potential efficacy to impede/halt disease progression.
Future Directions:
The discovery of novel and highly specific NOX inhibitors will provide opportunities to develop NOX inhibitors for treatment of fibrotic pathologies.
Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac fibrosis including mast cell stabilising compounds, rodents deficient in mast cells, and inhibition of the actions of mast cell-specific proteases such as chymase and tryptase. Whilst most evidence supports a pro-fibrotic role for mast cells, there is evidence that in some settings these cells can oppose fibrosis. A major gap in our current understanding of cardiac mast cell function is identification of the stimuli that activate these cells causing them to promote a pro-fibrotic environment. This review will present the evidence linking mast cells to cardiac fibrosis, as well as discuss the major questions that remain in understanding how mast cells contribute to cardiac fibrosis.
A large and growing portion of the human population, especially in developed countries, suffers one or more chronic, often quite burdensome ailments which either are overtly inflammatory in nature or are suspected to be of inflammatory origin, but for which investigations to date have failed to identify specific causes, let alone unifying mechanisms underlying the multiple such ailments that often afflict such patients. Relatively recently described as a non-neoplastic cousin of the rare hematologic disease mastocytosis, mast cell activation syndrome–suspected to be of greatly heterogeneous, complex acquired clonality in many cases–is a potential underlying/unifying explanation for a diverse assortment of inflammatory ailments. A brief review of mast cell biology and how aberrant primary mast cell activation might lead to such a vast range of illness is presented.
From the discovery of protease activated receptors (PARs) to the development of first clinically available PAR1 antagonist (vorapaxar) more than two decades of continuous research have passed. There are four different types of PARs named as PAR1, 2, 3 and 4 having a unique mechanism of signaling. These receptors are present in different organs, including the cardiovascular system. Presence of PARs in heart and blood vessels, alteration in the level and activity of the receptors in pathological conditions along with availability of antagonists makes these receptors targetable in several cardiac diseases. Therapeutic benefits of PAR antagonist have been proven in animal model of cardiac diseases such as myocardial infarction, viral myocarditis, atherosclerosis, pulmonary arterial hypertension, etc. PAR signaling plays a vital role in mediating cardiac hypertrophy, inflammation and fibrosis. Apart from having cardiac importance PAR antagonist are also continuously experimented for their beneficial effects in improving insulin resistance in metabolic syndromes. In the present review, we have discussed the functions of individual PARs in the heart and blood vessels along with the expected usefulness of PAR modulators in cardiovascular diseases.
Atherosclerosis is an inflammatory disease characterized by the accumulation of cholesterol in the arterial intima and consequently the formation of atherosclerotic plaques. Formation of these plaques is initiated by the appearance of macrophage foam cell in the arterial intima. Foam cells are formed as excessive cholesterol accumulates in the cytosol of macrophages and finally the net influx exceeds the efflux of cholesterol. Excessive accumulation of chemically modified cholesterol in foam cells finally leads to apoptosis and contributes to the formation of the lipid core in atherosclerotic plaques. The efflux of cholesterol from foam cells is essential for preventing the progression of atherosclerosis. The only unidirectional transporters ABCA1 and ABCG1, expressed on macrophages, transport intracellular cholesterol actively to distinct subpopulations of HDL. ApoA-I, the most important structural and functional component of nascent preβ-migrating HDL particles, receives cholesterol from ABCA1. Lipid-free HDL and apoA-I are sensitive to proteolytic modification leading to loss of function of these molecules. Functional apoA-I is essential for removal of cellular cholesterol and for cholesterol homeostasis. Cholesterol efflux initiates reverse cholesterol transport (RCT) which is the pathway for removal of cholesterol from the periphery for its final excretion into feces. The tiny fraction of total body-RCT that originates from the cholesterol-loaded macrophage foam cells located in the intima, is considered the only RCT component directly involved in atherosclerosis. Mast cells are bone marrow-derived inflammatory cells that are able to activate and secrete various mast cell mediators. Mast cells infiltrate the inflamed arterial intima where they can be activated through several stimuli present in the atherosclerotic intima. Mast cells release several inflammatory compounds of which histamine is probably the best known for its notorious effects in anaphylaxis. In addition to histamine and other vasoactive compounds, such as serotonin and bradykinin, mast cells release upon activation their unique serine proteases, tryptase and chymase. Chymase involvement in the progression of atherosclerosis has been suggested in a number of studies. Chymase is an enzyme capable of degrading LDL and HDL components leading to increased uptake of the modified LDL by macrophage foam cells or resulting in diminished cholesterol efflux, respectively. The purpose of this study was to evaluate whether mast cell-dependent HDL and apoA-I proteolysis would occur in vivo and whether such modification would alter the cholesterol efflux capacities of these cholesterol acceptors and finally affect the macrophage-specific RCT (mRCT). In the present study it was demonstrated for the first time that mast cell activation in vivo resulted in HDL proteolysis. Systemic mast cell activation led to the degradation of lipoprotein particles present in HDL and the entire preβ-HDL and α-HDL subpopulations were reduced in mouse serum following systemic mast cell activation. Systemic activation of mast cells in mice blunted the ability of serum and intraperitoneal fluid to promote cholesterol efflux from macrophage foam cells in vitro. Rat cardiac mast cell activation ex vivo led to the production of truncated apoA-I. ApoA-I was cleaved at the carboxyl-terminal region at Phe229 and Tyr192 or only at Tyr192 depending on the mast cell stimulus. Local peritoneal mast cell activation led to decreased ability of intraperitoneally injected apoA-I to promote macrophage cholesterol efflux in vitro. Furthermore treatment with intact lipid-free apoA-I but not chymase-treated apoA-I increased the overall mRCT from the peritoneal cavity to the intestinal contents within 3 hours. Importantly such an increase was fully blocked by the mast cell-specific degranulating compound 48/80 in mast cell-competent mice but not in mast cell-deficient mice. Interestingly local mast cell activation in the skin was able to promote mRCT from skin to feces. This was due to increased vascular permeability and influx of plasma HDL particles to skin consequently leading to increased mRCT. This stimulatory effect could be reproduced by the sole administration of the mast cell mediators, histamine, serotonin, and bradykinin. Importantly histamine treatment in apoA-I deficient mice was unable to promote mRCT. In conclusion, mast cell chymase is able to proteolyze HDL and lipid-free apoA-I reducing their abilities to promote cellular cholesterol efflux. Proteolysis of lipid-free apoA-I by rat cardiac mast cell chymase can occur within minutes and results in the formation of carboxyl-terminally truncated apoA-I. ApoA-I proteolysis in vivo results in reduced mRCT. Local mast cell activation in the skin results in increased mRCT due to increased availability of cholesterol acceptors in the vicinity of macrophage foam cells. These two seemingly opposite results underline the pleiotropic role of mast cells in the development of atherosclerosisAteroskleroosi eli valtimotauti on merkittävä kansanterveydellinen uhka Suomessa sekä muualla länsimaissa. Lihavuuden, metabolisen oireyhtymän ja diabeteksen yleistymisen vuoksi valtimotaudin riski on lisääntymässä myös muualla maailmassa. Valtimotaudille altistavat monet riskitekijät , joista useimmat liittyvät elämäntapoihin. Kolme merkittävintä valtimotaudin riskitekijää ovat tupakointi, suurentunut veren LDL-kolesteroli määrä ja kohonnut verenpaine. Kun pahan LDL-kolesterolin määrä lisääntyy veressä, alkaa sitä kertyä myös valtimoiden seinämiin. LDL-kolesterolin poistumista elimistöstä lisää veren hyvä HDL-kolesteroli. Veren alhainen HDL- kolesterolin määrä lisääkin riskiä sairastua valtimotautiin kun taas ja tavallista suurempi veren hyvän kolesterolin määrä pienentää taudin vaaraa. Mekanismia, jolla HDL-kolesteroli ehkäisee sepelvaltimotaudin syntyä, ei täysin tunneta. Potilaita mitatun HDL-kolesterolin määrä ei populaatiotutkimuksissa suoraan korreloi riskiin sairastua valtimotautiin. Kokeellisissa potilastutkimuksissa veren HDL-kolesterolin määrän nostaminen yksinomaan lääkkeellisesti ei ole todettu estävän valtimotaudin etenemistä. Näin ollen, pelkän HDL-kolesterolipitoisuuden mittaaminen ei anna koko kuvaa HDL-kolesterolin vaikutuksista, vaan HDL-partikkelien muulla rakenteella sekä toiminnalla on ilmeisesti suurempi merkitys. Tässä väitöskirjatutkimuksessa selvitettiin elimistön immuunijärjästelmään kuulvien syöttösolujen tuottamien entsyymien vaikutusta HDL-kolesterolin rakenneosasten toimintaan. HDL hiukkasen tärkein toiminnallinen osanen on pieni apolipoproteiiniA-1, joka lisää aktiivista kolesterolin poistumista soluista, joihin kolesterolia on kertynyt ylimäärin. Tämä kolesterolin poistuminen soluista on esimmäinen askel, jolla kolesterolia voidaan poistaa elimistöstä. Tutkimuksissa havaittiin, että syöttösolujen tuottama kymaasi-entsyymi hajotti HDL-kolesterolin rakenneosasia ja esti näin haitallisen kolesterolin poistumista soluista soluviljelmissä. Paikallinen vatsaontelon syöttösoluaktiviaatio aiheutti hiirille annostellun apoliproteiiniA-1:n hajoamisen ja vähensi kolesterolin poistumista elimistöstä. Kun apolipoproteiiniA-1:tä laitettiin virtaamaan eristettyjen rottien sydänten läpi, syöttösoluaktivaatio aiheutti lipoproteiinin pilkkoutumisen. Syöttösoluaktivaatio hiiren ihossa sai kuitenkin aikaan lisääntyneen kolesterolin poistumisen elimistöstä. Tämän tehostuneen poistumisen sai aikaan verisuonten läpäisevyyden lisääntyminen, joka johti HDL:n kerääntymiseen haitallista kolesterolia sisältävien solujen läheisyytteen. Lisääntynyt ihon HDL-kolesterolin määrä edesauttoi kolesterolin poistumista soluista ja näin edelleen elimistöstä. Sama ilmiö voitiin toistaa myös annostelemalla ihon alaisesti yksittäisiä syöttösolujen tuottamia tulehdustekijöitä. Tehdyissä tutkimuksissa havaittiin, että syöttösolujen tuottama kymaasi-entsyymi hajotti HDL:n rakenneproteiini apoliproteiiniA-1:tä ja esti näin kolesterolin poistumista soluista sekä elimistöstä. Toisaalta syöttösoluaktivaatio lisäsi paikallisesti kolesterolin poistumista ihosta. Tutkimustulokset osoittavat, että syöttösoluilla on moninaisia vaikutusia elimistön kolesterolitasapainoon. Yksittäisillä syöttösolujen tuottamilla tulehdustekijöillä havaittiin tutkimuksessa jopa vastakkaisia toimintoja. Jatkotutkimukset yksittäisten syöttösolujen tuottamien tulehdustekijöiden suhteesta kolesteroliaineenvaihduntaan ovatkin aiheellisia, jotta tutkimustuloksia voidaan hyödyntää valtimotaudin hoidossa.
The heart and the urinary bladder are hollow muscular organs, which can be afflicted by pressure overload injury due to pathological conditions such as hypertension and bladder outlet obstruction. This increased outflow resistance induces hypertrophy, marked by dramatic changes in the organs' phenotype and function. The end result in both the heart and the bladder can be acute organ failure due to advanced fibrosis and the subsequent loss of contractility. There is emerging evidence that microRNAs (miRNAs) play an important role in the pathogenesis of heart failure and bladder dysfunction. MiRNAs are endogenous non-coding single-stranded RNAs, which regulate gene expression and control adaptive and maladaptive organ remodeling processes. This Review summarizes the current knowledge of molecular alterations in the heart and the bladder and highlights common signaling pathways and regulatory events. The miRNA expression analysis and experimental target validation done in the heart provide a valuable source of information for investigators working on the bladder and other organs undergoing the process of fibrotic remodeling. Aberrantly expressed miRNA are amendable to pharmacological manipulation, offering an opportunity for development of new therapies for cardiac and bladder hypertrophy and failure.
The growth and differentiation of mast cells and melanocytes require stem cell factor (SCF), the ligand for the kit receptor
tyrosine kinase. SCF may exist as a membrane-bound or soluble molecule. Abnormalities of the SCF-kit signaling pathway, with
increased local concentrations of soluble SCF, have been implicated in the pathogenesis of the human disease cutaneous mastocytosis,
but have not yet been shown to play a causal role. To investigate both the potential of SCF to cause mastocytosis and its
role in epidermal melanocyte homeostasis, we targeted the expression of SCF to epidermal keratinocytes in mice with two different
transgenes controlled by the human keratin 14 promoter. The transgenes contained cDNAs that either produced SCF, which can
exist in both membrane-bound and soluble forms, or SCF, which remains essentially membrane bound. Murine epidermal keratinocyte
expression of membrane-bound/ soluble SCF reproduced the phenotype of human cutaneous mastocytosis, with dermal mast cell
infiltrates and epidermal hyperpigmentation, and caused the maintenance of a population of melanocytes in the interadnexal
epidermis, an area where melanocytes and melanin are found in human skin but where they are not typically found in murine
skin. Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and melanin production, but did not by
itself cause mastocytosis. We conclude, first, that a phenotype matching that of human mastocytosis can be produced in mice
by keratinocyte overproduction of soluble SCF, suggesting a potential cause of this disease. Second, we conclude that keratinocyte
expression of membrane-bound SCF results in the postnatal maintenance of epidermal melanocytes in mice. Since the resulting
animals have skin that more closely approximates human skin than do normal mice, their study may be more relevant to human
melanocyte biology than the study of skin of normal mice.
We compared cardiac mast cell (HHMC) density and the immunological and nonimmunological release of mediators from mast cells isolated from heart tissue of patients with idiopathic dilated (DCM) (n=24) and ischemic cardiomyopathy (ICM) (n = 10) undergoing heart transplantation and from control subjects (n = 10) without cardiovascular disease.
HHMC density in DCM (18.4+/-1.6 cells/mm2) and ICM (18.4+/-1.5 cells/mm2) was higher than that in control hearts (5.3+/-0.7 cells/mm2; P<.01). The histamine and tryptase contents of DCM and ICM hearts were higher than those of control hearts. The histamine content of the hearts was correlated with mast cell density (r(s)=.91; P<.001). Protein A/gold staining of heart tissue revealed stem cell factor (SCF), the principal growth, differentiating, and activating factor of human mast cells, in HHMC secretory granules. Histamine release from cardiac mast cells caused by immunological (anti-IgE and rhSCF) and nonimmunological stimuli (Ca2+ ionophore A23187) was higher in patients with DCM and ICM compared with control subjects. Immunological activation of HHMC induced a significantly greater release of tryptase and LTC4 in patients with DCM and ICM compared with control subjects.
Histamine and tryptase content and mast cell density are higher in failing hearts than in control hearts. SCF, present in secretory granules of HHMC, might represent an autocrine factor sustaining mast cell hyperplasia in heart tissue in these patients. The increased local release of fibrogenic factors (eg, histamine, tryptase, and leukotriene C4) might contribute to collagen accumulation in the hearts of patients with cardiomyopathy.
Transforming growth factor-beta (TGF beta) promotes deposition of extracellular matrix and is associated with fibrotic conditions both in experimental animals and in humans. Although a role for mast cells has been suspected in the pathogenesis of fibrosis, no potent mediator capable of stimulating fibroblast growth or extracellular matrix deposition has been identified in mast cell supernatants. We report here the constitutive production of TGF beta 1 by four dog mastocytoma cell lines. TGF beta 1 was identified by characteristic biologic activity, blockade of biologic effect by specific neutralizing antibody, and by recognition of a band with the appropriate migration by western blot. TGF beta 1 mRNA, but not TGF beta 2 or TGF beta 3 mRNA, was also produced constitutively by all four cell lines. Quantitation by bioassay revealed baseline TGF beta secretion of approximately 1 ng/10(6) cells over 48 h. Stimulation of mastocytoma cells with phorbol ester increased the rate of release of TGF beta 1, most markedly in the first 30 min after stimulation, without increasing TGF beta 1 mRNA. Dog mastocytoma cells produced TGF beta 1 primarily in a latent form, inactive until treated with acid. Both pure TGF beta 1 and TGF beta-containing mastocytoma cell-conditioned media inhibited mitogenesis and proliferation in dog mastocytoma cell lines, suggesting that mast cell tumor lines would not grow preferentially based on their ability to produce TGF beta. These studies may make possible further investigation of the mechanism by which mast cells contribute to the induction of fibrosis.
Although cachexia often accompanies advanced heart failure, little is known about the causes of the cachectic state. To assess the potential role of tumor necrosis factor in the pathogenesis of cardiac cachexia, we measured serum levels of the factor in 33 patients with chronic heart failure, 33 age-matched healthy controls, and 9 patients with chronic renal failure.
Mean (+/- SEM) serum levels of tumor necrosis factor were higher in the patients with heart failure (115 +/- 25 U per milliliter) than in the healthy controls (9 +/- 3 U per milliliter; P less than 0.001). Nineteen of the patients with chronic heart failure had serum levels of tumor necrosis factor greater than or equal to 39 U per milliliter (greater than 2 SD above the mean value for the control group), whereas the remaining 14 patients had serum levels of tumor necrosis factor below this level. The patients with high levels of tumor necrosis factor were more cachectic than those with low levels (82 +/- 3 vs. 95 +/- 6 percent of ideal body weight, respectively; P less than 0.05) and had more advanced heart failure, as evidenced by their higher values for plasma renin activity (2.92 +/- 0.53 vs. 1.06 +/- 0.53 ng per liter per second [10.5 +/- 1.9 vs. 3.8 +/- 1.9 ng per milliliter per hour]; P less than 0.01) and lower serum sodium concentration (135 +/- 1 vs. 138 +/- 1 mmol per liter; P less than 0.05). The group with high levels of tumor necrosis factor also had lower hemoglobin levels (7.82 +/- 0.2 vs. 8.69 +/- 0.4 mmol per liter [12.6 +/- 0.4 vs. 14.0 +/- 0.6 g per deciliter]) and higher values for blood urea nitrogen (19.5 +/- 2.2 vs. 12.5 +/- 1.8 mmol per liter) than the group with low levels of tumor necrosis factor (P less than 0.05 for both). The high levels of tumor necrosis factor were not due solely to decreased renal clearance, however, since the levels in the patients with heart failure were considerably higher than those in the nine patients with chronic renal failure (115 +/- 25 vs. 45 +/- 25 U per milliliter; P less than 0.05).
These findings indicate that circulating levels of tumor necrosis factor are increased in cachectic patients with chronic heart failure and that this elevation is associated with the marked activation of the renin-angiotensin system seen in patients with end-stage cardiac disease.
Mast cells play an essential role during development of inflammation after chemical and immunological insults and have been implicated in tissue fibrosis and angiogenesis. The exact contribution of mast cells to these conditions is largely unknown. In this study, we found that a potent angiogenic and mitogenic polypeptide, basic fibroblast growth factor (bFGF), is localized to the majority of mast cells from normal skin and lung and in tissue samples characterized by fibrosis, hyperplasia, and neovascularization. Using specific antibodies to mast cell tryptase, tissue macrophage, and bFGF, we demonstrate that cytoplasmic bFGF immunoreactivity is localized to 96.8 +/- 9.6% of tryptase-positive cells in human fibrotic lung tissue (n = 10), 82.3 +/- 6.9% of tryptase-positive cells in rheumatoid synovia (n = 6), and 93.1 +/- 4.8% of tryptase-positive cells in skin hemangioma (n = 5). Moreover, these tryptase-positive cells comprise a major portion (86 to 97%) of nonvascular cells exhibiting cytoplasmic bFGF staining in these tissues. In contrast, macrophage-like cells contribute less than 10% of the bFGF-positive cells in the same samples. The specificity of the immunostaining results was supported by the finding that cultured human mast cells (HMC-1) express both bFGF mRNA and protein. Our data indicate that mast cells, a primary source of heparin, also serve as a significant source of a heparin-binding growth factor, bFGF, in these disease processes. These observations suggest that mast cells may contribute to these pathological conditions by releasing this polypeptide.
Mast cell development in mice is critically regulated by stem cell factor (SCF), the term used here to designate a product of fibroblasts and other cell types that is a ligand for the tyrosine kinase receptor protein encoded by the proto-oncogene c-kit. However, the factors which regulate the size of mast cell populations in primates are poorly understood. Here we report that the subcutaneous administration of recombinant human SCF (rhSCF) to baboons (Papio cynocephalus) or cynomolgus monkeys (Macaca fascicularis) produced a striking expansion of mast cell populations in many anatomical sites, with numbers of mast cells in some organs of rhSCF-treated monkeys exceeding the corresponding values in control monkeys by more than 100-fold. Animals treated with rhSCF did not exhibit clinical evidence of mast cell activation, and discontinuation of treatment with rhSCF resulted in a rapid decline of mast cell numbers nearly to baseline levels. These findings are the first to demonstrate that a specific cytokine can regulate mast cell development in primates in vivo. They also provide the first evidence, in any mammalian species, to indicate that the cytokine-dependent expansion of tissue mast cell populations can be reversed when administration of the cytokine is discontinued.
To evaluate the potential relationship of mast cells with myocardial fibrosis in the cardiac ventricles of spontaneously hypertensive rats (SHR).
Experiments were performed on hearts from 36-week-old SHR with established left ventricular hypertrophy (n = 12) and from 36-week-old normotensive Wistar-Kyoto (WKY) rats (n = 12). Furthermore, to evaluate whether antihypertensive treatment with the angiotensin converting enzyme inhibitor quinapril interferes with the potential relationship between mast cells and fibrosis in SHR, we treated 16-week-old SHR (n = 12) with oral quinapril (10 mg/kg body weight per day) for 20 weeks.
Mast cells were counted in 25 high-power fields. Toluidine blue-stained sections and avidin staining were used to detect mast cells. The extent of myocardial fibrosis was analysed in samples stained with Masson's trichrome. The amount of collagen was evaluated morphometrically, using an automatic image analyser, and biochemically, using myocardial hydroxyproline concentration.
In the left ventricle of untreated SHR compared with age- and sex-matched normotensive WKY rats we found more extensive interstitial and perivascular fibrosis, an increased collagen volume fraction, an increased hydroxyproline concentration and an increased number of mast cells. Similar but less intense abnormalities were observed in the right ventricles of untreated SHR compared with the left ventricles of the same rats. In the left ventricles of quinapril-treated SHR compared with those of untreated SHR we found a marked decrease in fibrosis, a lower collagen volume fraction, a lower hydroxyproline concentration and fewer mast cells. Treatment with quinapril was also accompanied by normalization in the myocardial structure of the right ventricles of SHR. A positive correlation was found between the density of mast cells and the collagen volume fraction in the left ventricles of all of the rats.
The present findings suggest that mast cells can play a part in the development of the myocardial fibrosis that occurs in the cardiac ventricles with hypertensive cardiac hypertrophy. In addition, the present results suggest that the ability of quinapril to interfere with mast cells might be involved in its cardioreparative properties.
The biosynthesis of proteins containing cysteine-rich domains requires chaperones for their correct folding. For instance, the 39-kDa receptor-associated protein (RAP) aides in the cell-surface targeting of newly synthesized members of the mammalian low density lipoprotein receptor (LDLR) gene family, which contains tandemly arranged clusters of hexacysteine repeats. In the chicken, an LDLR relative with eight such repeats is expressed as two different splice variant forms in cell type-specific fashion (Bujo, H., Lindstedt, K. A., Hermann, M., Mola Dalmau, L., Nimpf, J., and Schneider, W. J. (1995) J. Biol. Chem. 270, 23546-23551). To learn more about evolutionary aspects of RAP, its role in escorting of these different receptor splice variants, and other potential functions, we have extended our studies on the avian LDLR family to RAP. cDNA cloning, determination of tissue expression at both the transcript and the protein level, stable expression in COS cells, and binding studies with chicken RAP revealed that mammalian RAPs have retained many features of the non-amniotic proteins. However, structural details, e.g. the well defined internal triplicate repeats in the chicken protein, have been somewhat diluted during evolution. Interestingly, chicken RAP was found to correlate positively with the expression levels in somatic cells of the larger splice variant of the eight-cysteine repeat receptor, but not with those of the smaller variant, expressed only in germ cells. This is compatible with the possibility that RAP may play a role in receptor biology that could be complementing its function in assisting folding. Chicken RAP in crude extracts of the stable expressor COS cells is able to bind to LDLR relatives in ligand blots without requirement for prior purification of the ligand. Thus, in conjunction with the avian model of massive lipid transport to germ cells, these cells provide a novel comparative system amenable to investigation of the biological functions of RAP.
Chymase is responsible for the formation of angiotensin II, which plays crucial roles in the pathogenesis of cardiovascular diseases. In the present study we determined the gene organization of a novel hamster chymase (hamster chymase 2) and analysed the expression of chymase 1, chymase 2 and angiotensin-converting enzyme (ACE) in hamster hearts at the terminal stage of cardiomyopathy. The gene encoding hamster chymase 2 is 3.2 kb in length and has five exons and four intervening sequences. The overall organization of this gene is similar to that of several other serine proteases. The deduced amino acid sequence revealed the existence of a preproenzyme composed of a signal peptide with 19 amino acids, a propeptide with two amino acids and a catalytic domain with 226 amino acids. The predicted full sequence of the catalytic domain was revealed to be very similar to the sequences of mouse mast-cell protease 5 (86%), rat mast-cell protease III (85%) and human chymase (70%) and less similar to hamster chymase 1 (56%). The expression of chymase 1 in heart was higher than that of chymase 2. The cardiac chymase-like activity, as well as the mRNA levels of chymase 1 and 2 of BIO 14.6 cardiomyopathic hamsters at the age of 60 weeks were increased 3.4-, 2.8- and 5.1-fold respectively compared with age-matched BIO F1B control hamsters. The cardiac ACE activity and the ACE mRNA level of cardiomyopathic hamsters were also increased 4.1- and 2.4-fold compared with those of age-matched controls. These results suggest that up-regulation of both ACE and chymases participates in the pathophysiology of the terminal stage of cardiomyopathy.
The nucleotide sequence data reported will appear in the DDBJ, EMBL and GenBank Nucleotide Sequence Databases under the accession number AB007622.
As a source of transforming growth factor beta1 (TGF-beta1), mast cells have been implicated as potential effector cells in many pathological processes. However, the mechanisms by which mast cells express, secrete, and activate TGF-beta1 have remained vague. We show here by means of RT-PCR, immunoblotting, and immunocytochemistry that isolated rat peritoneal mast cells synthesize and store large latent TGF-beta1 in their chymase 1-containing secretory granules. Mast cell stimulation and degranulation results in rapid secretion of the latent TGF-beta1, which is converted by chymase 1 into an active form recognized by the type II TGF-beta serine/threonine kinase receptor (TbetaRII). Thus, mast cells secrete active TGF-beta1 by a unique secretory mechanism in which latent TGF-beta1 and the activating enzyme chymase 1 are coreleased. The activation of latent TGF-beta1 specifically by chymase was verified using recombinant human latent TGF-beta1 and recombinant human chymase. In isolated TbetaRI- and TbetaRII-expressing peritoneal macrophages, the activated TGF-beta1 induces the expression of the plasminogen activator inhibitor 1 (PAI-1), whereas in the mast cells, the levels of TbetaRI, TbetaRII, and PAI-1 expression were below detection. Selective stimulation of mast cells in vivo in the rat peritoneal cavity leads to rapid overexpression of TGF-beta1 in peritoneal mast cells and of TbetaRs in peritoneal macrophages. These data strongly suggest that mast cells can act as potent paracrine effector cells both by secreting active TGF-beta1 and by enhancing its response in target cells.
Mast cells are believed to be involved in the pathophysiology of heart failure, but their precise role in the process is unknown. This study examined the role of mast cells in the progression of heart failure, using mast cell-deficient (WBB6F1-W/W(v)) mice and their congenic controls (wild-type [WT] mice). Systolic pressure overload was produced by banding of the abdominal aorta, and cardiac function was monitored over 15 wk. At 4 wk after aortic constriction, cardiac hypertrophy with preserved left ventricular performance (compensated hypertrophy) was observed in both W/W(v) and WT mice. Thereafter, left ventricular performance gradually decreased in WT mice, and pulmonary congestion became apparent at 15 wk (decompensated hypertrophy). In contrast, decompensation of cardiac function did not occur in W/W(v) mice; left ventricular performance was preserved throughout, and pulmonary congestion was not observed. Perivascular fibrosis and upregulation of mast cell chymase were all less apparent in W/W(v) mice. Treatment with tranilast, a mast cell-stabilizing agent, also prevented the evolution from compensated hypertrophy to heart failure. These observations suggest that mast cells play a critical role in the progression of heart failure. Stabilization of mast cells may represent a new approach in the management of heart failure.
Whether alcohol-induced heart failure is caused by a direct toxic effect of ethanol, metabolites, or whether it is a secondary result of neurohumoral, hormonal, or nutritional factors is not clear. To address this question a Langendorff retrograde coronary perfusion model of rat heart was used to study the effect of 0.5% (v/v) ethanol (n = 7) and 0.5 mM acetaldehyde (n = 9) on left ventricular expression of ANP, BNP, p53, p21, TNF-alpha,bax, bcl-2 as well as on DNA-fragmentation. Ethanol infusion of 150 min duration significantly induced both ANP and p21 mRNA expression of ventricular myocardium compared with hearts infused with vehicle (n = 8). Acetaldehyde did not exert any significant effects on any of the parameters studied, although the mean expression of TNF-alpha tended to be lower in the acetaldehyde-treated hearts than in control hearts. No evidence of increased DNA-fragmentation was found in ethanol or acetaldehyde treated groups. We conclude that ethanol per se is capable of inducing genes associated with hypertrophy and impaired function of the heart whereas a significant apoptosis is not involved in the initial phase of alcohol-induced cardiac injury.
The heart is a tumor necrosis factor (TNF)-producing organ. Both myocardial macrophages and cardiac myocytes themselves synthesize TNF. Accumulating evidence indicates that myocardial TNF is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Indeed, locally (vs. systemically) produced TNF contributes to postischemic myocardial dysfunction via direct depression of contractility and induction of myocyte apoptosis. Lipopolysaccharide or ischemia-reperfusion activates myocardial P38 mitogen-activated protein (MAP) kinase and nuclear factor kappa B, which lead to TNF production. TNF depresses myocardial function by nitric oxide (NO)-dependent and NO-independent (sphingosine dependent) mechanisms. TNF activation of TNF receptor 1 or Fas may induce cardiac myocyte apoptosis. MAP kinases and TNF transcription factors are feasible targets for anti-TNF (i.e., cardioprotective) strategies. Endogenous anti-inflammatory ligands, which trigger the gp130 signaling cascade, heat shock proteins, and TNF-binding proteins, also control TNF production and activity. Thus modulation of TNF in cardiovascular disease represents a realistic goal for clinical medicine.
A series of 96 posttransplant endomyocardial biopsies taken from 11 patients was subjected to quantitative analysis of mast cells and fibrosis. Ultrastructural analysis showed that mast cell numbers were increased and there was obvious degranulation in some posttransplant hearts. Activated mast cells and their secreted products, which contain heparin and histamine, are toxic to the hearts and may contribute to interstitial and perimyocytic fibrosis. The numbers of mast cells and granules were correlated with volume of fibrosis (r = 0.63, P less than 0.025; r = 0.73, P less than 0.01). There were differences between the release of mast cell granule contents seen in the posttransplant hearts and the rapid and massive reaction of anaphylactic degranulation of mast cells. Some mast cells progressively lost their dense granule contents, displaying a variety of piecemeal degranulation that indicates a slow degranulation process. These events occurred from the first week; they lasted from weeks to months. The fibrosis developed quickly in the cases with more mast cells and degranulation. The cases with fewer mast cells and granules showed only mild increases in the volume of fibrosis. Mast cells appeared as early as the first posttransplantation week. Patients with greater numbers of mast cells underwent more severe rejection episodes. This study demonstrated that mast cells play an early and important role in the perimyocytic and interstitial fibrosis of posttransplant hearts. Mast cells may also be important in the inflammatory process of rejection reaction. The severity of fibrosis appears related to the density of mast cells and their granules.
Mast cells in rat hearts were studied quantitatively during normal postnatal growth and in two types of cardiac hypertrophy. Normally, cardiac mast cell density in 11-12-day-old animals is very low, but increases markedly in the following 2-3 weeks to its highest values, with a subsequent decline toward adult values. At the peak of mast cell density, the percentage of mast cells in close proximity to capillaries is also highest. In adult animals, mast cell counts are significantly higher in the right ventricle than in the left. This relation is preserved even when the right ventricle is hypertrophic, as in rats born at simulated high altitude. Chronic hypertension and swimming have little effect on the mast cell density in rat hearts. Conspicuous changes in the mast cell density at the time of capillary proliferation seem to indicate a special role played by these cells in the formation of new vessels.
Tumour necrosis factor-alpha (TNF-alpha)/cachectin is a multifunctional cytokine that has effects in inflammation, sepsis, lipid and protein metabolism, haematopoiesis, angiogenesis and host resistance to parasites and malignancy. TNF-alpha was first described in activated macrophages, but certain mouse or rat mast cell populations (reviewed in refs 4,5) and some in vitro-derived human cells with cytochemical features of mast cells-basophils may also contain products similar to TNF-alpha. Here we present evidence that resident mouse peritoneal mast cells constitutively contain large amounts of TNF-alpha bioactivity, whereas cultured, immature mast cells vary in their TNF-alpha content. IgE-dependent activation of cultured or peritoneal mast cells induces extracellular release of TNF-alpha and augments levels of TNF-alpha messenger RNA and bioactivity. These findings identify mouse mast cells as an important source of both preformed and immunologically inducible TNF-alpha, and suggest that release of TNF-alpha by mast cells may contribute to host defence, the pathophysiology of allergic diseases and other processes dependent on TNF-alpha.
Although a great deal has been learned about the mediators produced by mast cells, the ultimate biologic function(s) of mast cell remains a mystery. Histamine, LTC4, PAF, and possibly tryptase (C3a generation) all enhance vasopermeability. Mediators with anticoagulant activities such as heparin and tryptase (fibrinogenolysis) and antithrombotic activity, PGD2, would appear to facilitate dispersion in tissues of the plasma ultrafiltrate brought there by the subgroup of mediators that enhance vasopermeability. In contrast, PAF causes platelet aggregation and chymase may cause arteriolar vasoconstriction (decreasing the volume of plasma reaching venules) by generation of angiotensin II. Assessment of any differential production of mediators by different types of mast cells will be of obvious importance in sorting out the physiologic responses to mast cell activation as well as the pathophysiology of allergic reactions.
Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.
Mast cells, a cell type involved in inflammatory reactions, are present in coronary atheromas and localize to the erosion or rupture site of atheromas in myocardial infarction. Here we report the presence of TNF-alpha, a proinflammatory cytokine, in mast cells of human coronary atheromas.
From samples of 37 coronary arteries from subjects autopsied for medicolegal reasons, sections of the bifurcation area of the left coronary artery were stained immunohistochemically for mast cells and TNF-alpha. In addition, macrophages, T lymphocytes, smooth muscle cells, and endothelial cells were investigated for their content of TNF-alpha. In normal intimas and fatty streaks, none of the cell types studied were TNF-alpha-positive. In 14 of the 24 atheromas found, TNF-alpha-positive cells were present. Of the total number of mast cells, 23% stained for TNF-alpha; of the macrophages, 1.3%; and of the smooth muscle cells, 0.4%. The majority (55%) of TNF-alpha-positive mast cells in the atheromas were located in the shoulder region and the remaining 35% in the cap and 10% in the core regions. Immunoelectron microscopy showed that the TNF-alpha in mast cells resided within their cytoplasmic secretory granules, demonstrating that these cells contain stores of TNF-alpha that will be released on degranulation.
This study demonstrates the presence of mast cells with TNF-alpha-containing secretory granules, particularly in the shoulder region of human coronary atheromas. By releasing their TNF-alpha, mast cells may play an active role in the inflammatory reactions of these rupture-prone areas of atheromas.
Myocardial infarction is associated with an intense inflammatory reaction leading to healing and scar formation. Because mast cells are a significant source of fibrogenic factors, we investigated mast cell accumulation and regulation of stem cell factor (SCF), a potent growth and tactic factor for mast cells, in the healing myocardium.
Using a canine model of myocardial ischemia and reperfusion, we demonstrated a striking increase of mast cell numbers during the healing phase of a myocardial infarction. Mast cell numbers started increasing after 72 hours of reperfusion, showing maximum accumulation in areas of collagen deposition (12.0+/-2.6-fold increase; P<0.01) and proliferating cell nuclear antigen (PCNA) expression. The majority of proliferating cells were identified as alpha-smooth muscle actin-positive myofibroblasts or factor VIII-positive endothelial cells. Mast cells did not appear to proliferate. Using a nuclease protection assay, we demonstrated induction of SCF mRNA within 72 hours of reperfusion. Immunohistochemical studies demonstrated that a subset of macrophages was the source of SCF immunoreactivity in the infarcted myocardium. SCF protein was not found in endothelial cells and myofibroblasts. Intravascular tryptase-positive, FITC-avidin-positive, CD11b-negative mast cell precursors were noted in the area of healing and in the cardiac lymph after 48 to 72 hours of reperfusion.
Mast cells increase in number in areas of collagen deposition and PCNA expression after myocardial ischemia. The data provide evidence of mast cell precursor infiltration into the areas of cellular injury. SCF is induced in a subset of macrophages infiltrating the healing myocardium. We suggest an important role for SCF in promoting chemotaxis and growth of mast cell precursors in the healing heart.
Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). TNF-alpha-converting enzyme (TACE) has recently been purified and its complementary DNA cloned. The expression of TACE results in the production of a functional enzyme that has precursor TNF-alpha in the mature form. The aim of this study was to determine whether TACE is expressed with TNF-alpha in myocardium and whether levels of TACE and TNF-alpha are related to clinical severity of DCM.
Endomyocardial tissues were obtained from 30 patients with DCM and 5 control subjects. TNF-alpha and TACE mRNA levels were measured by a novel real-time quantitative reverse transcriptase-polymerase chain reaction method. Expression of TNF-alpha and TACE proteins was determined by immunohistochemical analysis. TNF-alpha mRNA was expressed in DCM patients (TNF-alpha/GAPDH ratio 0.85+/-0.24) but not in control subjects. TACE mRNA expression was significantly greater in DCM patients than in control subjects (TACE/GAPDH ratio 2.52+/-0.59 vs 0.03+/-0.02, P<0.05). A positive correlation was found between TNF-alpha and TACE mRNA levels (r=0.779, P<0.001). TACE and TNF-alpha immunostaining was observed in myocytes in patients with DCM. When 2 subgroups of DCM were divided on the basis of left ventricular end-systolic diameter (LVESD) of 45 mm and left ventricular ejection fraction (LVEF) of 40%, the DCM subgroup with high LVESD (>/=45 mm) showed significantly greater expression of TACE (P=0.02) and TNF-alpha (P=0. 001) than did the low LVESD subgroup (<45 mm). In addition, the DCM subgroup with lower LVEF (<40%) showed higher expression of TACE (P=0.006) and TNF-alpha (P=0.01) than did the subgroup with high LVEF (>/=40%).
This study has shown that increased myocardial TACE expression is associated with elevated myocardial TNF-alpha expression in both mRNA and protein levels in clinically advanced DCM.
Acute increases in blood pressure (BP) increase myocardial tumor necrosis factor (TNF)-alpha production, but it is not known whether chronic hypertensive stress elevates myocardial TNF-alpha production, possibly contributing to cardiac remodeling, decreased cardiac function, and faster progression to heart failure. BP, cardiac function, and size were evaluated in normotensive [Sprague-Dawley (SD)], spontaneously hypertensive (SHR), and spontaneously hypertensive heart failure-prone (SHHF) rats at 6, 12, 15, and 18 mo of age and in failing SHHF. Left ventricular tissues were evaluated for secretion of bioactive TNF-alpha and inhibition of TNF-alpha secretion by phosphodiesterase inhibitors. All ventricles secreted bioactive and immunoreactive TNF-alpha, but secretion decreased with age. SHR and SHHF rats secreted more TNF-alpha than SD rats at 6 mo of age, but only failing SHHF rats secreted significantly more TNF-alpha at 18 mo. Amrinone inhibited TNF-alpha secretion in all rats and was less potent but more efficacious than RO-201724 in all strains. TNF-alpha secretion correlated with BP and left ventricular mass in 6-mo-old rats, but this relationship disappeared with age. Results suggest that hypertension and/or cardiac remodeling is associated with elevated myocardial TNF-alpha, and, although hypertension, per se, did not maintain elevated cardiac TNF-alpha levels, SHHF rats increase TNF-alpha production during the end stages of failure.
An increase in mast cell (MC) numbers in hemopoietic tissues may be associated with (a) primary neoplastic MC disease (mastocytosis); (b) non-mast cell lineage myelogenous disorders (myelodysplastic or myeloproliferative syndromes and myeloid leukemias); or (c) reactive, i.e. non-clonal states (MC hyperplasia and reactive mastocytosis). However, the histologic discrimination between hyperplastic states and neoplastic MC proliferative disorders is sometimes very difficult. MC hyperplasia is characterized by a diffuse increase in mature, round or spindle-shaped, metachromatic MC that are loosely scattered throughout the tissue and do not form dense focal infiltrates, even in states of marked hyperplasia. However, loosely scattered MC are also a prominent feature of many cases of myelodysplastic syndromes and acute leukemia involving the MC lineage. In contrast, the demonstration of dense, focal and/or diffuse MC infiltrates can be regarded as indicative of primary MC disease/mastocytosis. In addition to the highly diagnostic focal MC infiltrates, mastocytosis may also present with a predominantly diffuse or a mixed (diffuse and focal) infiltration pattern. The relatively rare diffuse pattern is usually dominated by atypical, often hypogranulated or even non-metachromatic MC and is associated with the aggressive or frankly malignant subtypes of systemic mastocytosis and MC leukemia. Although the demonstration of MC infiltrates in Giemsa-stained tissue sections is still very important for the diagnosis of mastocytosis, immunohistochemical techniques using antibodies against MC-associated antigens such as tryptase or c-kit (CD117) are essential for the identification of highly atypical, hypogranulated MC, especially in MC leukemia, and for the detection of small and even minute MC infiltrates.
Studies of cardiac allograft arteriosclerosis, i.e., chronic rejection, have largely focused on mononuclear inflammatory cell infiltrates in the vascular wall and periphery of the occluded vessels. The purpose of this study was to investigate the role of mast cells in the development of acute and chronic rejection in rat cardiac allografts.
In the acute rejection model, transplant recipients were not treated with immunosuppressants, and the grafts were removed 5 days after transplantation at the time of severe acute rejection. In the chronic rejection model, the recipients were administered triple-drug immunosuppression, and the grafts were removed 90 days after transplantation.
During acute rejection, the number of mast cells was not increased, but the localization pattern differed from that of syngeneic grafts. In acute rejection, mast cells were located in the perivascular region of the allografts, but in syngeneic grafts, mast cells had a more interstitial location. In the chronic rejection model, the cardiac allografts with severe intimal thickening showed large numbers of mast cells at perivascular sites of occluded intramyocardial vessels and in the interstitium. Linear regression analysis revealed a significant correlation between the numbers of perivascular and interstitial mast cells and the intensity of intimal thickening. The majority of mast cells showed positive immunoreactivity to basic fibroblast growth factor (bFGF). Macrophage bFGF expression was not so prominent, but macrophages were more frequent in numbers. Tumor necrosis factor-alpha expression was detected mainly in macrophages and in only a few mast cells. When the intensity of arteriosclerosis was decreased by an increase in the intensity of immunosuppression, the numbers of intragraft mast cells and other mononuclear cells, and also the production of their respective cytokines, bFGF and tumor necrosis factor-alpha, gradually diminished.
Taken together, our data show that the intensity of intramyocardial mast cell infiltration was associated with the intensity of chronic inflammation and allograft arteriosclerotic changes, but not with acute rejection, and that mast cells, in addition to macrophages, are a major source of myocardial bFGF. The results also demonstrate that when the T-cell activation pathway is blocked using cyclosporin, the number of mast cells is decreased. Cyclosporin may have affected the cytokine production that interfered with both the mast cell-dependent initiation and the leukocyte- and mast cell-dependent amplification and progression of the immune responses influenced by mast cell-leukocyte cytokine cascades. bFGF produced by mast cells may contribute to enhanced inflammation, neovascularization, and fibrosis during cardiac allograft arteriosclerosis.
- Tumor necrosis factor (TNF)-alpha has been implicated in the pathophysiology of congestive heart failure. A strain of transgenic mice (TNF1.6) with cardiac-specific overexpression of TNF-alpha develop congestive heart failure.
To determine the effect of anti-TNF-alpha therapy in this model, we studied 3 groups: TNF1.6 mice treated with saline, wild-type mice treated with saline, and TNF1.6 mice treated with TNF-alpha neutralizing antibody (cV1q) from 6 to 12 weeks of age. We used echocardiography to compare cardiac hypertrophy, function, and catecholamine response at 12 weeks of age versus baseline (6 weeks). cV1q treatment did not limit cardiac hypertrophy, but it significantly improved basal fractional shortening and responsiveness to beta-adrenergic stimulation, and it limited development of cardiac dilation.
Blockade of TNF-alpha bioactivity by antibody therapy may both preserve cardiac function and partially reverse pathological changes in congestive heart failure.