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Pathogenesis of cardiac fibrosis: Ischemic injury to the heart is caused by coronary artery disease due to plaque formation and reduced blood supply. Ischemic injury is followed by a cascade of mechanism consisting of three overlapping phases, to heal the infarcted heart and results in cardiac fibrosis. a Plaque formation, b, c healed scar in a post MI heart with normal myocyte in upper portion of the image, and d collagen deposition
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Heart disease causing cardiac cell death due to ischemia–reperfusion injury is a major cause of morbidity and mortality in the United States. Coronary heart disease and cardiomyopathies are the major cause for congestive heart failure, and thrombosis of the coronary arteries is the most common cause of myocardial infarction. Cardiac injury is follo...
Citations
... However, many of the supporting data derived from non-human cardiac tissues have dubious applicability to human myocardium. Much of the literature on the pathophysiology of myocardial fibrosis has investigated laboratory animals under artificially created pathological models [26][27][28]. Animal models may help to understand disease processes and to find antifibrotic treatment options [28]. ...
... Much of the literature on the pathophysiology of myocardial fibrosis has investigated laboratory animals under artificially created pathological models [26][27][28]. Animal models may help to understand disease processes and to find antifibrotic treatment options [28]. ...
Background and Objectives: The combination of aortic valve stenosis (AS) and ischemic heart disease (IHD) is quite common and is associated with myocardial fibrosis (MF). The purpose of this study was to evaluate the association between the histologically verified left ventricular (LV) MF and its geometry and function in isolated AS and AS within IHD groups. Materials and Methods: In a single-center, prospective trial, 116 patients underwent aortic valve replacement (AVR) with/without concomitant surgery. The study population was divided into groups of isolated AS with/without IHD. Echocardiography was used, and LV measurements and aortic valve parameters were obtained from all patients. Myocardial tissue was procured from all study patients undergoing elective surgery. Results: There were no statistical differences between isolated AS and AS+IHD groups in LV parameters or systolic and diastolic functions during the study periods. The collagen volume fraction was significantly different between the isolated AS and AS+IHD groups and was 7.3 ± 5.6 and 8.3 ± 6.4, respectively. Correlations between MF and left ventricular end-diastolic diameter (LVEDD) (r = 0.59, p = < 0.001), left ventricular mass (LVM) (r = 0.42, p = 0.011), left ventricular ejection fraction (LVEF) (r = −0.67, p < 0.001) and an efficient orifice area (EOA) (r = 0.371, p = 0.028) were detected in isolated AS during the preoperative period; the same was observed for LVEDD (r = 0.45, p = 0.002), LVM (r = 0.36, p = 0.026), LVEF (r = −0.35, p = 0.026) and aortic annulus (r = 0.43, p = 0.018) in the early postoperative period; and LVEDD (r = 0.35, p ≤ 0.05), LVM (r = 0.43, p = 0.007) and EOA (r = 0.496, p = 0.003) in the follow-up period. In the group of AS and IHD, correlations were found only with LV posterior wall thickness (r = 0.322, p = 0.022) in the follow-up period. Conclusions: Histological MF in AS was correlated with LVM and LVEDD in all study periods. No correlations between MF and LV parameters were found in aortic stenosis in the ischemic heart disease group across all study periods.
... MF is initially a feature of cardiac remodeling which poses risks on patients over time and consequently leads to function impairment, morbidity and even mortality [24]. TP could exert potent pharmacological effects against fibrosis [25]. ...
Objective. Myocardial fibrosis (MF) is a common manifestation of end-stage cardiovascular diseases. Triptolide (TP) provides protection against cardiovascular diseases. This study was to explore the functional mechanism of TP in MF rats via the Wnt/β-catenin pathway. Methods. The MF rat model was established via subcutaneous injection of isoproterenol (ISO) and treated with low/medium/high doses of TP (L-TP/M-TP/H-TP) or Wnt agonist BML-284. Cardiac function was examined by echocardiography. Pathological changes of myocardial tissues were observed by HE and Masson staining. Col-I/Col-III/Vimentin/α-SMA levels were detected by immunohistochemistry, RT-qPCR, and Western blot. Collagen volume fraction content was measured. Expression levels of the Wnt/β-catenin pathway-related proteins (β-catenin/c-myc/Cyclin D1) were detected by Western blot. Rat cardiac fibroblasts were utilized for in vitro validation experiments. Results. MF rats had enlarged left ventricle, decreased systolic and diastolic function and cardiac dysfunction, elevated collagen fiber distribution, collagen volume fraction and hydroxyproline content. Levels of Col-I/Col-III/Vimentin/α-SMA, and protein levels of β-catenin/c-myc/Cyclin D1 were increased in MF rats. The Wnt/β-catenin pathway was activated in the myocardial tissues of MF rats. TP treatment alleviated impairments of cardiac function and myocardial tissuepathological injury, decreased collagen fibers, collagen volume fraction, Col-I, Col-III, α-SMA and Vimentin levels, HYP content, inhibited Wnt/β-catenin pathway, with H-TP showing the most significant effects. Wnt agonist BML-284 antagonized the inhibitive effect of TP on MF. TP inhibited the Wnt/β-catenin pathway to repress the proliferation and differentiation of mouse cardiac fibroblasts in vitro. Conclusions. TP was found to ameliorate ISO-induced MF in rats by inhibiting the Wnt/β-catenin pathway.
... Cardiac hypertrophy is the adaptive change of myocardium when the volume or pressure load increases, which is the response of cardiomyocytes to various physiological or pathological stimuli (Old eld et al., 2020). However, the progression of myocardial hypertrophy can lead to myocardial brosis, which can aggravate cardiovascular disease (Rai et al., 2017). Therefore, reduction of heart brosis is a signi cant factor in the treatment of cardiomyopathy . ...
The role of magnesium isoglycyrrhizinate (MgIG) in myocardial remodeling is being investigated. We evaluated the result of MgIG on isoproterenol (ISO) -enticed myocardial remodeling in mice by activating the PI3K/AKT1 pathway. The heart function of mice was tested by echocardiography, and it was found that MgIG could improve the left ventricular function. Pathological staining analysis showed that MgIG could decrease the degree of myocardial injury caused by ISO. The serum data detected by ELISA showed that MgIG could reduce the content of CK-MB, MDA and LDH, and increase the activity of GSH-Px. Western blotting showed that the protein expressions of Collagen Ⅰ, BNP, Bax, Cleaved caspase-3, p-PI3K and p-AKT1 were decreased, while the protein expressions of Bcl-2, COX2 and SOD1 were increased. Meanwhile activation of the PI3K activator (740Y-P) reverses the cardioprotective effect of MgIG. These findings suggest that the myocardial remodeling induced by ISO could be improved by MgIG, and its mechanism may be associated with inhibite PI3K/AKT1 pathway to regulate apoptosis and oxidative stress.
... Compared to the rest four organs, miR-455-5p level in heart was much higher, indicating that miR-455-5p may play an important role in heart (Fig. 1a). It is acknowledged that cardiac hypertrophy and cardiac fibrosis are two key phenotypes of pathological cardiac remodeling, and isoprenaline (ISO) can be employed to induce pathological cardiac remodeling in vitro [28][29][30]. Thus, we utilized ISO to construct cardiac hypertrophy model in NRCMs and cardiac fibrosis model in NRFBs. ...
... ISO is an effective reagent to induce pressure overload, and cardiac pressure overload is a common factor to provoke pathological cardiac remodeling [28], therefore, we chose ISO to construct cardiac remodeling model in vivo. Then, to figure out the level of miR-455-5p in vivo, mice were injected with specific oligonucleotides against miR-455-5p (miR-455-5p antagomir) or negative control oligonucleotides (NC antagomir) via tail vein. ...
Pathological cardiac remodeling plays an essential role in the progression of cardiovascular diseases, and numerous microRNAs have been reported to participate in pathological cardiac remodeling. However, the potential role of microRNA-455-5p (miR-455-5p) in this process remains to be elucidated. In the present study, we focused on clarifying the function and searching the direct target of miR-455-5p, as well as exploring its underlying mechanisms in pathological cardiac remodeling. We found that overexpression of miR-455-5p by transfection of miR-455-5p mimic in vitro or tail vain injection of miR-455-5p agomir in vivo provoked cardiac remodeling, whereas genetic knockdown of miR-455-5p attenuated the isoprenaline-induced cardiac remodeling. Besides, miR-455-5p directly targeted to 3’-untranslated region of protein arginine methyltransferase 1 (PRMT1) and subsequently downregulated PRMT1 level. Furthermore, we found that PRMT1 protected against cardiac hypertrophy and fibrosis in vitro. Mechanistically, miR-455-5p induced cardiac remodeling by downregulating PRMT1-induced asymmetric di-methylation on R1748, R1750, R1751 and R1752 of Notch1, resulting in suppression of recruitment of Presenilin, Notch1 cleavage, NICD releasing and Notch signaling pathway. Finally, circulating miR-455-5p was positively correlated with parameters of left ventricular wall thickening. Taken together, miR-455-5p plays a provocative role in cardiac remodeling via inactivation of the PRMT1-mediated Notch signaling pathway, suggesting miR-455-5p/PRMT1/Notch1 signaling axis as potential therapeutic targets for pathological cardiac remodeling.
... Stroke volume (SV) was significantly lower in mTAC mice compared to sham mice starting from the second week after surgery [ Table 1, P < 0.001]. Finally, the left ventricular posterior wall diastolic diameter (LVPW;d) was increased only at 2 weeks after surgery [ Figure 3G], consistent with the typical hypertrophic response, which is usually followed by progression to a decompensated dilated cardiomyopathy [15] . Subsequently, the LVPW;d and LVPW in systole (LVPW;s) were significantly lower in mTAC mice starting at 8-and 6-weeks post-surgery, respectively [ Figure 3G and H], indicative of LV dilatation associated with HF development. ...
Introduction:
Heart failure (HF) is the leading cause of death worldwide. Most large and small animal disease models of HF are based on surgical procedures. A common surgical technique to induce HF is transverse aortic constriction (TAC), which induces pressure overload. The conventional TAC (cTAC) procedure is a highly invasive surgery that is associated with severe inflammation and excessive perioperative deaths.
Aim:
To establish an improved, minimally invasive TAC (mTAC) procedure that does not require thoracotomy.
Methods and results:
Following anesthesia, mice were intubated, and a small incision was made at the neck and chest. After cutting the sternum about 4 mm, the aortic arch was approached without opening the pleural cavity. A suture was placed between the brachiocephalic artery and the left common carotid artery. This model was associated with low perioperative mortality and a highly reproducible constriction evidenced by an increased right-to-left carotid blood flow velocity ratio in mTAC mice (5.9 ± 0.2) vs. sham controls (1.2 ± 0.1; P < 0.001). mTAC mice exhibited progressive cardiac remodeling during the 8 weeks post-TAC, resulting in reduced left ventricular (LV) contractility, increased LV end-systolic diameter, left atrial enlargement and diastolic dysfunction, and an increased heart weight to tibia length ratio (mTAC: 15.0 ± 0.8 vs. sham: 10.1 ± 0.6; P < 0.01).
Conclusion:
Our data show that the mTAC procedure yields a highly reproducible phenotype consisting of LV contractile dysfunction and enlargement, combined with left atrial enlargement and diastolic dysfunction.
Potential impact of the findings:
This model may be used to test the molecular mechanisms underlying atrial remodeling associated with HF development or to evaluate therapeutic strategies to treat these conditions.
... The expression of Twist-related protein 2 (Twist2/Dermo1), and Engrailed1 (En1) regulate the differentiation of papillary and reticular dermal fibroblasts [14]. β regulates the phenotypic conversion of proto-myofibroblasts to myofibroblasts [15]. The functional and biological role of myofibroblasts during wound healing is modulated by the differential expression of ECM components including desmin, fibronectin, collagens, and matrix composition [7,16]. ...
... The expression of Twist-related protein 2 (Twist2/Dermo1), platelet-derived growth factor receptor α (PDGFRα), and Engrailed1 (En1) regulate the differentiation of papillary and reticular dermal fibroblasts [14]. Transforming growth factor (TGF)-β regulates the phenotypic conversion of proto-myofibroblasts to myofibroblasts [15]. The functional and biological role of myofibroblasts during wound healing is modulated by the differential expression of ECM components including desmin, fibronectin, collagens, and matrix composition [7,16]. ...
Non-healing diabetic foot ulcer, a chronic inflammatory disease, is a sizable clinical and economic burden to healthcare systems around the world. Chronic inflammation plays a critical role in the nonhealing pattern due to the arrest of the cellular response during wound healing in the inflammatory phase without progressing to the proliferative and remodeling phase. Fibroblasts play a critical role in all three phases of wound healing. Activation of fibroblasts in the presence of cytokines results in the formation of myofibroblast that contributes to extracellular matrix formation. Additionally, few studies documented the presence of inflammatory, angiogenic, and angiostatic fibroblast subpopulation during wound healing. Various studies have discussed the role of transcription factors and microRNA in regulating the transdifferentiation of fibroblast to myofibroblast, however, what factors regulate the reprogramming of fibroblast to inflammatory, angiogenic, and angiostatic phenotypes have not been clearly addressed in the literature. This critical review article addresses the role of transcription factors and microRNAs in regulating fibroblast to myofibroblast transdifferentiation followed by the prediction of transcription factors and microRNAs, based on the bioinformatics analysis, in regulating transdifferentiation of fibroblasts to inflammatory, angiogenic, and angiostatic subtypes. The results of in-silico networking revealed multiple new transcription factors and microRNAs and their interaction with specific markers on other fibroblasts suggesting their role in the regulation of fibroblast reprogramming.
... These findings in fibroblasts isolated from Sprague Dawley (SD) rats suggest that sex affects fibroblasts phenotype and the factors regulating fibroblasts phenotype warrant investigation. Fibroblast to myofibroblast conversion is mediated by TGF-β and this plays a crucial role during wound healing [45,46]. The differential expression of TGF-β and iNOS between male and female Sprague-Dawley rats in an inflammatory cystitis model further supports the notion of investigating the effects of sex on chronic wound healing associated with chronic inflammation [47]. ...
Treatment of nonhealing diabetic foot ulcers (DFUs) is a major clinical concern and challenge for clinicians. Despite the advancement in treatment strategies, there is no definitive treatment for complicated nonhealing DFUs. Animal models are crucial for understanding pathogenesis and investigating novel therapeutic small molecules and the rodent model is commonly used for research related to cutaneous wound healing. Sexual dimorphism and its effect on the efficacy of sex hormones in enhancing healing in cutaneous wounds using a rodent model have been discussed, however, there is a lack of data related to diabetic foot ulcers. Further, the effects of sexual dimorphism on the issues related to induction of diabetes, differential immune response, type and size of the wound, the effectiveness of topical versus systemic treatment, and molecular mechanisms involved in wound healing like hemostasis, granulation tissue formation, the response of keratinocytes and fibroblasts, inflammation, and skin anatomy are scarcely discussed. Understanding these aspects is of significance and will help in choosing the correct sex, species, and strain of rodents while investigating therapeutic small molecules for DFUs. This review critically summarized these issues and their translational aspects followed by highlighting the effect of sexual dimorphism on these important aspects.
... As discussed above, change in fibroblast phenotype is regulated by cytokines and growth factors secreted in the microenvironment or systemically having a paracrine effect. Transforming growth factor-β signaling plays a critical role in the transition of fibroblasts to myofibroblasts [88,89]. Additionally, changes in fibroblast phenotypes may also be regulated mechanically and physically. ...
... The presence of different populations of cell types, fibroblast plasticity, and interconvertible fibroblast subpopulations in the non-healing wound makes it difficult to characterize the fibroblast phenotypes and the molecular mechanism underlying this transition. Even with these concerns, investigating the underlying molecular mechanisms using animal models [88] and targeting the mediators associated with non-healing like CXCL-8 (IL-8) [8,21] and recruitment of immune cells [84] might be of therapeutic significance to improve clinical outcomes. Understanding the involved molecular mechanisms for the non-healing of wounds, in-depth, is particularly important because of its multifactorial pathogenesis involving aging, nutrition, hypoxia, stress, infections, drugs, genetics, and chronic diseases [121]. ...
Chronic diabetic foot ulcers (DFUs) are an important clinical issue faced by clinicians despite the advanced treatment strategies consisting of wound debridement, off-loading, medication, wound dressings, and keeping the ulcer clean. Non-healing DFUs are associated with the risk of amputation, increased morbidity and mortality, and economic stress. Neo-angiogenesis and granulation tissue formation are necessary for physiological DFU healing and acute inflammation play a key role in healing. However, chronic inflammation in association with diabetic complications holds the ulcer in the inflammatory phase without progressing to the resolution phase contributing to non-healing. Fibroblasts acquiring myofibroblasts phenotype contribute to granulation tissue formation and angiogenesis. However, recent studies suggest the presence of five subtypes of fibroblast population and of changing density in non-healing DFUs. Further, the association of fibroblast plasticity and heterogeneity with wound healing suggests that the switch in fibroblast phenotype may affect wound healing. The fibroblast phenotype shift and altered function may be due to the presence of chronic inflammation or a diabetic wound microenvironment. This review focuses on the role of fibroblast plasticity and heterogeneity, the effect of hyperglycemia and inflammatory cytokines on fibroblasts, and the interaction of fibroblasts with other cells in diabetic wound microenvironment in the perspective of DFU healing. Next, we summarize secretory, angiogenic, and angiostatic phenotypes of fibroblast which have been discussed in other organ systems but not in relation to DFUs followed by the perspective on the role of their phenotypes in promoting angiogenesis in DFUs.
... The main feature of HF has reduced contractile force or underfilling. Systemic inflammation, hypoxic environment, cardiomyocyte damage, mechanical stress, and other profibrotic cytokines, transforming fibroblasts into myofibroblasts at the injury site, are the essential pathophysiological processes underlying heart diseases [12]. Myofibroblasts have a more contractile structure by developing stress fibers. ...
... Overpressure-induced left ventricular hypertrophy and HF have been produced in rodents by transverse aortic constriction (TAC) and abdominal aortic constriction (AAC) [12,158,159]. Rats exposed to pressure-overload for more than 8 weeks have impaired systolic function, fractional shortening, and EF values. Significant increases in left ventricular posterior wall thickness, left ventricular inner size, and ventricular septal wall-size indicate concentric cardiac hypertrophy [10,143]. ...
... This experimental model uses 60% kilocalories from fat (lard) and drinking water with 0.5 g/L of L-NAME [252]. and CO Rat, mouse [8,11,12,16,26,65,84,154,220,222,223] Ischaemia/reperfusion injury Temporary LAD ligation Close to the clinical scenario with the occluded vessel's reperfusion during coronary angiography performed after an acute MI Surgery is more time consuming and more complex than the placement of permanent LAD ligation Increased LVEDP, LVESV, and N-terminal pro-BNP Rat, mouse [11,26] Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Heart failure (HF) is one of the most critical health and economic burdens worldwide, and its prevalence is continuously increasing. HF is a disease that occurs due to a pathological change arising from the function or structure of the heart tissue and usually progresses. Numerous experimental HF models have been created to elucidate the pathophysiological mechanisms that cause HF. An understanding of the pathophysiology of HF is essential for the development of novel efficient therapies. During the past few decades, animal models have provided new insights into the complex pathogenesis of HF. Success in the pathophysiology and treatment of HF has been achieved by using animal models of HF. The development of new in vivo models is critical for evaluating treatments such as gene therapy, mechanical devices, and new surgical approaches. However, each animal model has advantages and limitations, and none of these models is suitable for studying all aspects of HF. Therefore, the researchers have to choose an appropriate experimental model that will fully reflect HF. Despite some limitations, these animal models provided a significant advance in the etiology and pathogenesis of HF. Also, experimental HF models have led to the development of new treatments. In this review, we discussed widely used experimental HF models that continue to provide critical information for HF patients and facilitate the development of new treatment strategies.
... 1,2 Due to the high prevalence and clinical relevance of heart failure (HF) syndrome, several studies have described different models for analyzing this condition. [3][4][5] In this context, experimental HF models should mimic the major pathophysiological and morphological changes detected in humans, including cardiac remodeling, reduced ventricular function, hemodynamic changes such as reduced cardiac output and increased systemic vascular resistance, and histopathological changes. Over the last decades, several experimental models of acute and chronic HF with reduced ejection fraction have been developed to reproduce different aspects of dilated cardiomyopathy, a condition that can be induced by different events such as volume overload, 6 pressure overload by aortic constriction, 7 induction of arterial hypertension, 8 tachycardiomyopathy, 9,10 acute myocardial infarction, 11,12 and the use of cardiotoxic drugs such as propranolol, imipramine, and doxorubicin. ...
Abstract
Background: Doxorubicin (DOXO) has been used to induce dilated cardiomyopathy (DCM) in experimental models.
Objective: To analyze cardiac changes after DOXO infusion and define the most effective protocol to reproduce an
experimental model of DCM.
Methods: Male Wistar rats were divided into 4 groups and received increasing cumulative doses of DOXO (at a
rate of 2 mg/kg/week) or saline solution: the control group (CTR) received saline solution, Group D-8 received a
total infusion of 8 mg/kg, Group D-12 received 12 mg/kg, and Group D-16 received 6 mg/kg. All animals underwent
echocardiography at baseline and after the end of infusion. The animals were then euthanized and cardiac tissue
was collected for histological analysis.
Results: Mortality rates were 20% (D-8), 30% (D-12), and 67.6% (D-16). The 8 mg/kg dose was not associated with a
significant reduction in left ventricular ejection fraction (LVEF) or an increase in left ventricular end-diastolic diameter
(LVEDD). There was significant LVEF impairment with 12 mg/kg and 16 mg/kg doses compared to the control (68.3±5%
vs 58.4±9%, p < 0.01, for CTR-12 vs D-12; and 66.0±6% vs 47.6±15%, p < 0.01, for CTR-16 vs D-16). Histological
analyses revealed a greater percentage of fibrosis in D-12 (10.6±3.3%) and D-16 (9.8±2.3%) compared to CTR
(2.3±1.0%), p < 0.001.
Conclusions: The DOXO dose of 16 mg/kg was associated with severe cardiac changes and high mortality. Thus, we propose
a DOXO dose of 12 mg/kg as the most appropriate and effective for inducing DCM with an acceptable mortality rate.
