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Osteopontin-deficiency leads to cardiomyocyte loss and poor left ventricular function. (a) Osteopontin mRNA-expression in whole WT-mouse hearts during repetitive I/R and (b) in Langendorff-isolated adult WT-cardiomyocytes after 3 days I/R compared to sham. (c) Representative HE-stained section of WT-heart after 7 days I/R shows interstitial cellular infiltration in contrast to (d) irreversible loss of cardiomyocytes in OPN⁻/⁻-mice (arrow). (e) Fractional shortening was impaired in both strains, but loss of left ventricular contractility was significantly reduced in OPN⁻/⁻-mice after 7 d I/R compared to WT. (f) Anterior wall thickening was significantly reduced in OPN⁻/⁻-mice after 7 days I/R. n = 8 – 11 /group. Scale bars represent 50 μ m. RT-qPCR using Taqman and mRNA-expression is related to controls and GAPDH using comparative Δ Δ Ct-method. Bracket indicates P ≤ 0.05 between genotypes; * indicates P ≤ 0.05 versus respective shams.
Source publication
Repetitive brief ischemia and reperfusion (I/R) is associated with ventricular dysfunction in pathogenesis of murine ischemic cardiomyopathy and human hibernating myocardium. We investigated the role of matricellular protein osteopontin-1 (OPN) in murine model of repetitive I/R. One 15-min LAD-occlusion followed by reperfusion was performed daily o...
Citations
... In the last two decades, several studies utilizing osteopontin depletion either by neutralizing antibodies or by targeted mutagenesis have further advanced our understanding of the role of osteopontin in various cardiac pathologies [59,[67][68][69][70][71][72]. Osteopontin-null mice were used in a number of HF models, including angiotensin-II (Ang-II) infusion [59], al-dosterone infusion [67], transverse aortic constriction (TAC) [68], desmin-deficient model of dilated cardiomyopathy (DCM) [69], streptozotocin-induced model of diabetic cardiomyopathy [70], left anterior descending artery (LAD) ligation as a model of myocardial infarction (MI) [71] and a brief, repetitive LAD-occlusion model of ischemia-reperfusion (IR)-induced myocardial injury [72]. ...
... In the last two decades, several studies utilizing osteopontin depletion either by neutralizing antibodies or by targeted mutagenesis have further advanced our understanding of the role of osteopontin in various cardiac pathologies [59,[67][68][69][70][71][72]. Osteopontin-null mice were used in a number of HF models, including angiotensin-II (Ang-II) infusion [59], al-dosterone infusion [67], transverse aortic constriction (TAC) [68], desmin-deficient model of dilated cardiomyopathy (DCM) [69], streptozotocin-induced model of diabetic cardiomyopathy [70], left anterior descending artery (LAD) ligation as a model of myocardial infarction (MI) [71] and a brief, repetitive LAD-occlusion model of ischemia-reperfusion (IR)-induced myocardial injury [72]. However, these and other studies have yielded conflicting results suggesting disease-and cell-specific roles of osteopontin in cardiac pathologies. ...
The matricellular protein osteopontin modulates cell–matrix interactions during tissue injury and healing. A complex multidomain structure of osteopontin enables it not only to bind diverse cell receptors but also to interact with various partners, including other extracellular matrix proteins, cytokines, and growth factors. Numerous studies have implicated osteopontin in the development and progression of myocardial remodeling in diverse cardiac diseases. Osteopontin influences myocardial remodeling by regulating extracellular matrix production, the activity of matrix metalloproteinases and various growth factors, inflammatory cell recruitment, myofibroblast differentiation, cardiomyocyte apoptosis, and myocardial vascularization. The exploitation of osteopontin loss- and gain-of-function approaches in rodent models provided an opportunity for assessment of the cell- and disease-specific contribution of osteopontin to myocardial remodeling. In this review, we summarize the recent knowledge on osteopontin regulation and its impact on various cardiac diseases, as well as delineate complex disease- and cell-specific roles of osteopontin in cardiac pathologies. We also discuss the current progress of therapeutics targeting osteopontin that may facilitate the development of a novel strategy for heart failure treatment.
... Studies suggest a cardioprotective role for OPN following ischemic insults [69,70], and OPN-null mice developed greater cardiac dilatation following MI, which was associated with reduced collagen production [71]. OPN-null mice subjected to repeated ischemic-reperfusion injury developed small, non-transmural infarctions and ventricular dysfunction due to cardiomyocyte loss, compared to WT controls [74]. OPN-null mice had reduced expression of tenascin-C (TN-C), MMP-9, MMP-12 and TIMP-1, but higher expression of MMP-13. ...
The extracellular matrix (ECM) and ECM-regulatory proteins mediate structural and cell-cell interactions that are crucial for embryonic cardiac development and postnatal homeostasis, as well as organ remodeling and repair in response to injury. These proteins possess a broad functionality that is regulated by multiple structural domains and dependent on their ability to interact with extracellular substrates and/or cell surface receptors. Several different cell types (cardiomyocytes, fibroblasts, endothelial and inflammatory cells) within the myocardium elaborate ECM proteins, and their role in cardiovascular (patho)physiology has been increasingly recognized. This has stimulated robust research dissecting the ECM protein function in human health and disease and replicating the genetic proof-of-principle. This review summarizes recent developments regarding the contribution of ECM to cardiovascular disease. The clear importance of this heterogeneous group of proteins in attenuating maladaptive repair responses provides an impetus for further investigation into these proteins as potential pharmacological targets in cardiac diseases and beyond.
... Among these factors, longevity, self-renewal, proliferation, and survival-associated factors, such as Fgf-21, G-Csf, Chi3l1, Lif, and Gas6 [50][51][52][53][54][55] were identified in the young ECM (Fig. 2C). Cardioprotection, cardiac function, ECM remodeling, and antioxidation-associated factors, such as Pedf, Ptx3, Il-33, Pdecgf, and Opn [56][57][58][59][60] were present at high levels in the adult ECM (Fig. 2D). Finally, fibrosis, post-MI cardiac remodeling, and hypertrophy associated factors such as Cxcl9, Il10, Il11, aFgf [61][62][63][64] were high in the aged ECM (Fig. 2E). ...
Cardiovascular diseases are the leading cause of death worldwide and their occurrence is highly associated with
age. However, lack of knowledge in cardiac tissue aging is a major roadblock in devising novel therapies. Here,
we studied the effects of cell and cardiac extracellular matrix (ECM) aging on the induced pluripotent stem cell
(iPSC)-derived cardiomyocyte cell state, function, as well as response to myocardial infarction (MI)-mimicking
stress conditions in vitro. Within 3-weeks, young ECM promoted proliferation and drug responsiveness in young
cells, and induced cell cycle re-entry, and protection against stress in the aged cells. Adult ECM improved cardiac
function, while aged ECM accelerated the aging phenotype, and impaired cardiac function and stress defense
machinery of the cells. In summary, we have gained a comprehensive understanding of cardiac aging and
highlighted the importance of cell-ECM interactions. This study is the first to investigate the individual effects of
cellular and environmental aging and identify the biochemical changes that occur upon cardiac aging.
... Cardioprotection, cardiac function, ECM remodeling, and antioxidation-associated factors, such as Pedf, Ptx3, Il-33, Pdecgf, and Opn [56][57][58][59][60]were present at high levels in the adult ECM (Fig. 2D). Finally, fibrosis, post-MI cardiac remodeling, and hypertrophy associated factors such as Cxcl9, Il10, Il11, aFgf [61][62][63][64] were high in the aged ECM (Fig. 2E). ...
Cardiovascular diseases are the leading cause of death worldwide and their occurrence is highly associated with age. However, lack of knowledge in cardiac tissue aging is a major roadblock in devising novel therapies. Here, we studied the effects of cell and cardiac extracellular matrix (ECM) aging on the induced pluripotent stem cell (iPSC)-derived cardiomyocyte cell state, function, as well as response to myocardial infarction (MI)-mimicking stress conditions in vitro . Within 3-weeks, young ECM promoted proliferation and drug responsiveness in young cells, and induced cell cycle re-entry, and protection against stress in the aged cells. Adult ECM improved cardiac function, while aged ECM accelerated the aging phenotype, and impaired cardiac function and stress defense machinery of the cells. In summary, we have gained a comprehensive understanding of cardiac aging and highlighted the importance of cell-ECM interactions. This study is the first to investigate the individual effects of cellular and environmental aging and identify the biochemical changes that occur upon cardiac aging.
... Macrophages contribute to the outcome of various types of CVD, including myocardial tissue fibrosis and rheumatic heart disease [8,9]. Under normal conditions, most of the macrophages that reside in myocardial tissues are derived from embryonic hematopoietic activity and possess the ability to maintain the tissue through self-renewal [10,11]. ...
Cardiovascular diseases (CVD) remain one of the leading causes of mortality worldwide, especially in developing countries. It is widely known that severe inflammation can lead to atherosclerosis, which can cause various downstream pathologies, including myocardial injury and viral myocarditis. To date, several strategies have been proposed to prevent and cure CVD. The use of targeting macrophages has emerged as one of the most effective therapeutic approaches. Macrophages play a crucial role in eliminating senescent and dead cells while maintaining myocardial electrical activity and repairing myocardial injury. They also contribute to tissue repair and remodeling and plaque stabilization. Targeting macrophage pathways can, therefore, be advantageous in CVD care since it can lead to decreased aggregation of mononuclear cells at the injured site in the heart. Furthermore, it inhibits the development of pro-inflammatory factors, facilitates cholesterol outflow, and reduces the lipid concentration. More in-depth studies are still needed to formulate a comprehensive classification of phenotypes for different macrophages and determine their roles in the pathogenesis of CVD. In this review, we summarize the recent advances in the understanding of the role of macrophages in the prevention and cure of CVD.
... At the same time this adaptation was malfunctional in our model, as revealed by small areas of dense collagen deposition indicating replacement fibrosis due to cardiomyocyte loss [7,42]. The significant increase in tenascin C expression seems to be linked to this increased collagen deposition, due to its function during early tissue remodeling [43,44]. Our previous work using Cnr2 − / − -mice in a model of repetitive RT-qPCR using Taqman®, mRNA expression is related to shams and GAPDH using comparative ΔΔCt-method; brackets indicate P ≤ 0.05 between the genotypes; * indicate P ≤ 0.05 vs. respective sham; d, days. ...
Aims: Pulmonary hypertension (PH) leads to right ventricular (RV) adaptation and remodeling and has deleterious long-term effects on RV function. The endocannabinoid receptor CB2 has been associated with protective effects in adaptation and remodeling of the left ventricle after ischemia. Therefore, we investigated the role of CB2 receptor in RV adaptation after occlusion of the left pulmonary artery (LPA) in a murine model. Main methods: C57/Bl6 (WT)- and CB2 receptor-deficient (Cnr2⁻/⁻)-mice underwent paramedian sternotomy and LPA was occluded using a metal clip. Right heart hemodynamic study (Millar®) preceded organ harvesting for immunohistochemistry and mRNA analysis 7 and 21 days (d) post-occlusion. Key findings: LPA occlusion led to higher RV systolic pressure in Cnr2⁻/⁻-hearts, while hemodynamics were comparable with WT-hearts after 21d. Cnr2⁻/⁻-hearts showed higher macrophage infiltration and lower interleukin-10 expression after 7 d, but otherwise a comparable inflammatory mediator expression profile. Cardiomyocyte-hypertrophy was stronger in Cnr2⁻/⁻-mice, presenting with higher tenascin-C expression than WT-hearts. Planimetry revealed higher collagen area in Cnr2⁻/⁻-hearts and small areas of cardiomyocyte-loss. Surrounding cardiomyocytes were cleaved caspase-3- and TUNEL positive in Cnr2⁻/⁻-hearts. This was associated by maladaptation of myosin heavy-chain isoforms and lower reactive oxygen scavenger enzymes induction in Cnr2⁻/⁻-hearts. We found comparable morphological changes in both lungs between the two genotypes. Significance: LPA occlusion led to increased systolic pressure and adaptation of RV in CB2-deficient mice. CB2 receptor seems to modulate RV adaptation through expression of contractile elements, reactive oxygen scavenger enzymes, and inflammatory response in order to prevent cardiomyocyte apoptosis.
... In a chronic cardiac fibrosis model, OPN was necessary for the AP1-mediated induction of pro-fibrotic miR-21 [65]. On the contrary, OPN was found to be protective in AMI models, either by promoting fibroblast migration and collagen expression through its N-terminal domain, or by inducing antioxidative mediators, chemokines, and cardiomyocyte contraction [66,67]. In animal models of renal fibrosis, OPN was expressed by injured epithelial cells and it was shown to be regulated by transcriptional activation through AP-1 and to enhance the macrophage recruitment and the pro-fibrotic phenotype of pericytes [68][69][70][71]. ...
Purpose of Review
This review intends to outline the novel findings on the effects of matricellular proteins in the development of organ fibrosis and present recent advances towards a potential usage of matricellular proteins as markers or targets of therapy for fibrotic diseases.
Recent Findings
Recent studies elucidated the sites of production of different matricellular proteins during fibrosis of several organs, their specific binding receptors, and their effects on different cell types. For some proteins, a differential function between chronic disease and acute injury and a connection to regulation of inflammatory cell subtypes with relevance to fibrosis was established.
Summary
Matricellular proteins have evolved as important mediators in the progression of fibrosis. Several studies have already depicted their potential as biomarkers of the disease stage and evolution in patients, while the evaluation of their utility as therapeutic targets has been limited in animal models of fibrosis. This knowledge should guide future research on the development of drugs to treat fibrosis.
... We identified the presence of reactive oxygen species [3] and of the chemokine CCL2 [4] to be important for development of interstitial fibrosis without a loss of cardiomyocytes. In following studies we were able to depict mechanisms of cardioprotection and found an irreversible loss of cardiomyocytes and deteriorated cardiac function in mice deficient in endocannabinoid receptor CB2 [5] and in matricellular glycoprotein osteopontin 1 [6]. In both studies, the cardiomyocyte loss was associated with a significantly lower expression of metalloprotein MT1 and MT2, in contrast to their persistent induction in the WT-mice. ...
... In order to ascertain the amplification of a single PCR product, dissociation curve analysis was performed. The mRNA expression was related to shams and GAPDH using comparative ΔΔCtmethod [6,19]. ...
Aims
. Repetitive brief ischemia and reperfusion (
I
/
R
) is associated with left ventricular dysfunction during development of ischemic cardiomyopathy. We investigated the role of zinc-donor proteins metallothionein MT1 and MT2 in a closed-chest murine model of
I
/
R
.
Methods
. Daily 15-minute LAD-occlusion was performed for 1, 3, and 7 days in SV129 (WT)- and MT1/2 knockout (M
T
-
/
-
)-mice (
n
= 8–10/group). Hearts were examined with M-mode echocardiography and processed for histological and mRNA studies.
Results
. Expression of MT1/2 mRNA was transiently induced during repetitive
I
/
R
in WT-mice, accompanied by a transient inflammation, leading to interstitial fibrosis with left ventricular dysfunction without infarction. In contrast, M
T
-
/
-
-hearts presented with enhanced apoptosis and small infarctions leading to impaired global and regional pump function. Molecular analysis revealed maladaptation of myosin heavy chain isoforms and antioxidative enzymes in MT1/
2
-
/
-
-hearts. Despite their postponed chemokine induction we found a higher total neutrophil density and macrophage infiltration in small infarctions in M
T
-
/
-
-hearts. Subsequently, higher expression of osteopontin 1 and tenascin C was associated with increased myofibroblast density resulting in predominately nonreversible fibrosis and adverse remodeling in MT1/
2
-
/
-
-hearts.
Conclusion
. Cardioprotective effects of MT1/2 seem to be exerted via modulation of contractile elements, antioxidative enzymes, inflammatory response, and myocardial remodeling.
... In I/R model, OPN expression was found to be associated with cardiac myocytes. Mice lacking OPN exhibited reduced LV function following I/R (Duerr et al., 2014). Although this study did not measure apoptosis, however, mice lacking OPN exhibited reduced anterior wall thickness. ...
Heart failure represents a major cause of morbidity and mortality in the western society. Cardiac myocyte loss due to apoptosis plays a significant role in the progression of heart failure. The extracellular matrix (ECM) maintains the structural integrity of the heart and allows the transmission of electrical and mechanical signals during cardiac contraction and relaxation. Matricellular proteins, a class of non-structural ECM proteins, play a significant role in ECM homeostasis and intracellular signaling via their interactions with cell surface receptors, structural proteins, and/or soluble extracellular factors such as growth factors and cytokines. Osteopontin (OPN), also called cytokine Eta-1, is a member of matricellular protein family. Normal heart expresses low levels of OPN. However, OPN expression increases markedly under a variety of pathophysiological conditions of the heart. Many human and transgenic mice studies provide evidence that increased OPN expression, specifically in myocytes, associates with increased myocyte apoptosis and myocardial dysfunction. This review summarizes OPN expression in the heart, and its role in myocyte apoptosis and myocardial function.
Macrophages are immuno cells with high flexibility among hematopoietic system. Macrophages are tangled with many diseases like chronic inflammatory, atherosclerosis, autoimmune, and cancer. Macrophages play a major role in developing the inflammation and meanwhile resolving the damage occurred during these disease conditions. Therefore, the use of macrophages in targeted drug delivery appeared to be a promising approach in modifying the microenvironment of inflammatory diseases. The macrophages with cellular backpacks loaded with drugs were appeared to be the effective drug transporter to the brain inflammation. Till date, among the different carrier systems emerged among macrophage targeting: liposomes, microspheres, nanoparticles, and dendrimers were extensively studied. The physicochemical properties like components, lipophilicity, hydrophilicity, ligand presence, and concentration of these carriers may vary the efficacy and specificity of drug targeting to macrophages. The present review provides an insight into M1 and M2 macrophages characteristics, mainly discussed the role of macrophages in regulating several inflammatory diseases. This article underlines the current status and application of different carriers for targeted drug delivery to macrophages along with their efficacy and specificity. In general, the targeted drug delivery was achieved using the carrier systems by removing the intrinsic pathway and bio protection which is offered to the therapeutic molecules. Further, the review also summarizes the newer approaches for macrophage targeting with a brief overview on recent advances and future prospects.
