scholarly journals Extracellular Superoxide Dismutase (EC-SOD) Regulates Gene Methylation and Cardiac Fibrosis During Chronic Hypoxic Stress

2020 ◽  
Author(s):  
Ayan Rajgarhia ◽  
Kameshwar Ayyasola ◽  
Nahla Zaghloul ◽  
Jorge M. Lopez Da Re ◽  
Edmund J. Miller ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Extracellular Superoxide Dismutase ◽  
Hypoxic Stress ◽  
Gene Methylation ◽  
Alpha Smooth Muscle Actin ◽  
Extra Copy ◽  
Rassf1a Gene ◽  
Hypoxic Group

AbstractBackgroundChronic hypoxic stress induces epigenetic modifications in cardiac fibroblasts, such as inactivation of tumor suppressor genes (RASSF1A), and activation of kinases (ERK1/2). The effects of the antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), on these epigenetic changes has not been fully explored.ObjectivesTo define the effect of EC-SOD overexpression on cardiac fibrosis induced by chronic hypoxia.MethodsWild type C57B6 male mice (WT) and transgenic males with an extra copy of human hEC-SOD (TG) were housed in hypoxia (10% O2) for 21 days. Right ventricular tissue was studied for cardiac fibrosis markers using RT-PCR and Western Blot analyses. Downstream effects were studied, for both RASSF-1 expression and methylation and its relation to ERK1/2, using in-vivo & in-vitro modelsResultsThere were significant increases in markers of cardiac fibrosis : Collagen 1, Alpha Smooth Muscle Actin (ASMA) and SNAIL, in the WT hypoxic animals as compared to the TG hypoxic group (p< 0.05). Expression of DNA methylation enzymes (DNMT 1,2) was significantly increased in the WT hypoxic mice as compared to the hypoxic TG mice (p<0.001). RASSF1A expression was significantly lower and ERK1/2 was significantly higher in hypoxia WT compared to the hypoxic TG group (p<0.05). Use of SiRNA to block RASSF1A gene expression in murine cardiac fibroblast tissue culture led to increased fibroblast proliferation (p<0.05). Methylation of RASSF1A promoter region showed a significant reduction in the TG hypoxic group compared to the WT hypoxic group (0.59 vs 0.75 respectively).ConclusionsEC-SOD significantly attenuates RASSF1A gene methylation, and plays a pivotal role cardiac fibrosis induced by hypoxia.

scholarly journals Extracellular Superoxide Dismutase (EC-SOD) Regulates Gene Methylation and Cardiac Fibrosis During Chronic Hypoxic Stress

2021 ◽  
Vol 8 ◽  
Author(s):  
Ayan Rajgarhia ◽  
Kameshwar R. Ayasolla ◽  
Nahla Zaghloul ◽  
Jorge M. Lopez Da Re ◽  
Edmund J. Miller ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tissue Culture ◽  
Superoxide Dismutase ◽  
Cardiac Fibrosis ◽  
Extracellular Superoxide Dismutase ◽  
Hypoxic Stress ◽  
Fibroblast Proliferation ◽  
Gene Methylation ◽  
Hypoxic Group

Chronic hypoxic stress induces epigenetic modifications mainly DNA methylation in cardiac fibroblasts, inactivating tumor suppressor genes (RASSF1A) and activating kinases (ERK1/2) leading to fibroblast proliferation and cardiac fibrosis. The Ras/ERK signaling pathway is an intracellular signal transduction critically involved in fibroblast proliferation. RASSF1A functions through its effect on downstream ERK1/2. The antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), decreases oxidative stress from chronic hypoxia, but its effects on these epigenetic changes have not been fully explored. To test our hypothesis, we used an in-vitro model: wild-type C57B6 male mice (WT) and transgenic males with an extra copy of human hEC-SOD (TG). The studied animals were housed in hypoxia (10% O2) for 21 days. The right ventricular tissue was studied for cardiac fibrosis markers using RT-PCR and Western blot analyses. Primary C57BL6 mouse cardiac fibroblast tissue culture was used to study the in-vitro model, the downstream effects of RASSF-1 expression and methylation, and its relation to ERK1/2. Our findings showed a significant increase in cardiac fibrosis markers: Collagen 1, alpha smooth muscle actin (ASMA), and SNAIL, in the WT hypoxic animals as compared to the TG hypoxic group (p &lt; 0.05). The expression of DNA methylation enzymes (DNMT 1&amp;3b) was significantly increased in the WT hypoxic mice as compared to the hypoxic TG mice (p &lt; 0.001). RASSF1A expression was significantly lower and ERK1/2 was significantly higher in hypoxia WT compared to the hypoxic TG group (p &lt; 0.05). Use of SiRNA to block RASSF1A gene expression in murine cardiac fibroblast tissue culture led to increased fibroblast proliferation (p &lt; 0.05). Methylation of the RASSF1A promoter region was significantly reduced in the TG hypoxic group compared to the WT hypoxic group (0.59 vs. 0.75, respectively). Based on our findings, we can speculate that EC-SOD significantly attenuates RASSF1A gene methylation and can alleviate cardiac fibrosis induced by hypoxia.

scholarly journals Extracellular Superoxide Dismutase (EC-SOD) Regulates Gene Methylation and Cardiac Fibrosis During Chronic Hypoxic Stress

2020 ◽  
Author(s):  
Ayan Rajgarhia ◽  
Kameshwar Ayyasola ◽  
Nahla Zaghloul ◽  
Jorge M. Lopez Da Re ◽  
Edmund J. Miller ◽  
...  
Keyword(s):  
Dna Methylation ◽  
In Vitro Model ◽  
Cardiac Fibrosis ◽  
Extracellular Superoxide Dismutase ◽  
Hypoxic Stress ◽  
Fibroblast Proliferation ◽  
Gene Methylation ◽  
Vitro Model ◽  
Hypoxic Group

Abstract Background: Chronic hypoxic stress induces epigenetic modifications mainly DNA methylation in cardiac fibroblasts, inactivating tumor suppressor genes (RASSF1A), and activating kinases (ERK1/2) leading to fibroblast proliferation and cardiac fibrosis. The Ras/ERK signaling pathway is an intracellular signal transduction critically involved in fibroblast proliferation. RASSF1A functions through its effect on downstream ERK1/2. The antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), decreases oxidative stress from chronic hypoxia but it’s effects on these epigenetic changes has not been fully explored. Objectives: In-vitro model: Wild type C57B6 male mice (WT) and transgenic males with an extra copy of human hEC-SOD (TG) were housed in hypoxia (10% O2) for 21 days. Right ventricular tissue was studied for cardiac fibrosis markers using RT-PCR and Western Blot analyses. in-vitro model, downstream effects of RASSF-1 expression and methylation and its relation to ERK1/2, were studied using primary C57BL6 mouse cardiac fibroblast tissue culture.Results: There were significant increases in markers of cardiac fibrosis : Collagen 1, Alpha Smooth Muscle Actin (ASMA) and SNAIL, in the WT hypoxic animals as compared to the TG hypoxic group (p< 0.05). Expression of DNA methylation enzymes (DNMT 1,2) was significantly increased in the WT hypoxic mice as compared to the hypoxic TG mice (p<0.001). RASSF1A expression was significantly lower and ERK1/2 was significantly higher in hypoxia WT compared to the hypoxic TG group (p<0.05). Use of SiRNA to block RASSF1A gene expression in murine cardiac fibroblast tissue culture led to increased fibroblast proliferation (p<0.05). Methylation of RASSF1A promoter region was significantly reduced in the TG hypoxic group compared to the WT hypoxic group (0.59 vs 0.75 respectively). Conclusions: EC-SOD significantly attenuates RASSF1A gene methylation and can alleviate cardiac fibrosis induced by hypoxia.

scholarly journals The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

2021 ◽  
Vol 22 (4) ◽  
pp. 1861
Author(s):  
Jemima Seidenberg ◽  
Mara Stellato ◽  
Amela Hukara ◽  
Burkhard Ludewig ◽  
Karin Klingel ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Beclin 1 ◽  
Type I ◽  
Alpha Smooth Muscle Actin

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown. Methods and Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis. Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.

Abstract P107: Hypertension Enhances the Differentiation of Cardiac Fibroblasts Into Myofibroblasts After TGF-beta1 Treatment

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Gianluca L Perrucci ◽  
Maria Corlian!ò ◽  
Delfina Tosi ◽  
Patrizia Nigro ◽  
Gaetano Bulfamante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Pcr Analysis ◽  
Alpha Smooth Muscle Actin ◽  
Qrt Pcr ◽  
Gene And Protein Expression

Objectives: In cardiac fibrosis associated with hypertension, TGF-beta1 plays a key role by acting on differentiation of cardiac fibroblasts (CF) into alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts. In this study, we tested the effect of TGF-beta1 during the myofibroblast differentiation process of CF from normotensive and hypertensive rats. Methods: CF were obtained by enzymatic digestion of hearts isolated from Spontaneously Hypertensive (hCF) and normotensive Wistar Kyoto (nCF) rats (n=5 rat/group). Gene and protein expression in CF was evaluated by Western blot and qRT-PCR analyses, respectively. Immunohistochemistry analysis for integrin alpha-v beta-5 was performed on rat cardiac tissue (n=5 rat/group). Results: Cultured hCF showed an enhanced SMAD2/3 activation and alpha-SMA protein expression after treatment with TGF-beta1 (5 ng/ml) in comparison with nCF. Alpha-SMA up-regulation was further confirmed by qRT-PCR analysis that showed a significant increase in alpha-SMA gene expression in hCF after TGF-beta1 treatment (2.78±0.25 vs 2.01±0.21 fold increase, p <0.05). Moreover, immunostaining on cardiac tissues revealed a higher expression of integrin alpha-v beta-5 in hypertensive vs normotensive rat hearts (345.3±170.0 vs 48.2±22.3 mm 2 of integrin-positive area, p <0.05). This result was also confirmed in vitro ; indeed, integrin alpha-v beta-5 gene expression in hCF increased 2.8-fold in basal condition and 5.12-fold after TGF-beta1 treatment when compared to untreated nCF. Conclusions: Taken together, these results suggest that hCF are more prone to upregulate integrin alpha-v beta-5 and consequently differentiate into myofibroblasts in vitro under TGF-beta1 treatment. Thus, targeting alpha-v beta-5 might open a novel prospective for the treatment of fibrosis in hypertensive hearts likely reducing integrin-mediated TGF-beta1 activation.

Abstract 305: E2F1 Suppresses Cardiac Fibrosis

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Dauren Biyashev ◽  
Chan Boriboun ◽  
Gangjian Qin
Keyword(s):  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Mouse Heart ◽  
Wild Type ◽  
Alpha Smooth Muscle Actin ◽  
Embryonic Fibroblasts ◽  
Smad 3 ◽  
Regulation Of Cell Cycle

E2F1 transcription factor is best known for regulation of cell cycle; its role in the cardiovascular system is not well understood. In a transcriptome analysis, we detected a significantly elevated level in the expression of collagen I and alpha-smooth muscle actin in the E2F1-null (E2F1-/-) mouse embryonic fibroblasts (MEFs) as compared to wild-type (WT) MEFs. Levels of Smad 2 and Smad 3 were also significantly higher in E2F1-/- MEFs. In addition, treatment with TGF-beta (10 ng/ml) induced a greater degree of Smad 2 and Smad 3 phosphorylation in E2F1-/- MEFs than in WT MEFs. Interestingly, these in vitro observations were corroborated with our results obtained from mouse heart samples: the basal levels of both total and phosphorylated Smad 2 were significantly higher in the E2F1-/- heart than in the WT heart (n=3). To understand the significance of these findings in the pathogenesis of cardiac fibrosis, we administered Angiotensin II (3 mg/kg/day) to animals for 7 or 14 days with a subcutaneous osmotic minipump. The total area of cardiac fibrosis was significantly greater in the E2F1-/- mice than in WT littermates (E2F1-/- vs. WT: 17+/-3.8% vs. 6+/-2.6%, p<0.05). Thus, we disclose a novel role of E2F1 in the control of Smad signaling that may limit the development of fibrosis in the stressed heart.

scholarly journals Dec1 Deficiency Suppresses Cardiac Perivascular Fibrosis Induced by Transverse Aortic Constriction

2019 ◽  
Vol 20 (19) ◽  
pp. 4967 ◽  
Author(s):  
Le ◽  
Sato ◽  
Kohsaka ◽  
Bhawal ◽  
Nakao ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Transforming Growth Factor Beta ◽  
Calcium Binding ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Alpha Smooth Muscle Actin ◽  
Circadian Expression

Cardiac fibrosis is a major cause of cardiac dysfunction in hypertrophic hearts. Differentiated embryonic chondrocyte gene 1 (Dec1), a basic helix–loop–helix transcription factor, has circadian expression in the heart; however, its role in cardiac diseases remains unknown. Therefore, using Dec1 knock-out (Dec1KO) and wild-type (WT) mice, we evaluated cardiac function and morphology at one and four weeks after transverse aortic constriction (TAC) or sham surgery. We found that Dec1KO mice retained cardiac function until four weeks after TAC. Dec1KO mice also revealed more severely hypertrophic hearts than WT mice at four weeks after TAC, whereas no significant change was observed at one week. An increase in Dec1 expression was found in myocardial and stromal cells of TAC-treated WT mice. In addition, Dec1 circadian expression was disrupted in the heart of TAC-treated WT mice. Cardiac perivascular fibrosis was suppressed in TAC-treated Dec1KO mice, with positive immunostaining of S100 calcium binding protein A4 (S100A4), alpha smooth muscle actin (αSMA), transforming growth factor beta 1 (TGFβ1), phosphorylation of Smad family member 3 (pSmad3), tumor necrosis factor alpha (TNFα), and cyclin-interacting protein 1 (p21). Furthermore, Dec1 expression was increased in myocardial hypertrophy and myocardial infarction of autopsy cases. Taken together, our results indicate that Dec1 deficiency suppresses cardiac fibrosis, preserving cardiac function in hypertrophic hearts. We suggest that Dec1 could be a new therapeutic target in cardiac fibrosis.

scholarly journals Phosphocreatine Attenuates Isoproterenol-Induced Cardiac Fibrosis and Cardiomyocyte Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Hui Dai ◽  
Liang Chen ◽  
Dongyue Gao ◽  
Aihua Fei
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Cardiomyocyte Apoptosis ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Type I ◽  
Alpha Smooth Muscle Actin

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-β1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.

Abstract 121: Interleukin 11 Mediates Wnt/β-catenin-dependent Fibrotic Response Of Human Cardiac Fibroblasts

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Edyta Dzialo ◽  
Marcin Czepiel ◽  
Maciej Siedlar ◽  
Gabriela Kania ◽  
Przemyslaw Blyszczuk
Keyword(s):  
Smooth Muscle ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Neutralizing Antibody ◽  
Cell Culture Supernatant ◽  
Muscle Actin ◽  
Alpha Smooth Muscle Actin ◽  
Wnt Proteins ◽  
Human Cardiac Fibroblasts

Wnt proteins family represents secreted glycoproteins implicated in the number of fibrotic cardiac pathologies. The transcriptional activity of Wnts is broad and involves β-catenin-dependent or β-catenin-independent responses. In this study, we examined the effect of exogenous Wnt3a (β-catenin-dependent) and Wnt5a (β-catenin-independent) in TGF-β-activated human cardiac fibroblasts. Furthermore, we assessed the hypothesis that Wnt3a could regulate IL-11 production and analyzed its contribution to profibrotic response in cardiac fibroblasts.By employing a full genome transcriptomics, we analyzed transformation of human cardiac fibroblasts induced by TGF-β in the presence of Wnt3a or Wnt5a produced by cell culture supernatant of L-Wnt3a, L-Wnt5a or control L-cells. Stimulation with Wnt3a of TGF-β-activated fibroblasts resulted in induction of 66 genes, specifically involved in myofibroblast differentiation including ACTA2 (encoding alpha smooth muscle actin; αSMA) ACTG2 (encoding gamma smooth muscle actin; γSMA) and VCL (encoding vinculin). In contrast to Wnt3a, treatment with Wnt5a upregulated expression of only 2 genes in TGF-β-activated cells. Additionally, in the presence of TGF-β, Wnt3a enhanced phosphorylation of TAK1 and production and secretion of IL-11. Importantly, in the absence of TGF-β, Wnt3a did not promote fibroblast-to-myofibroblast transition, TAK1 phosphorylation and IL-11 production. To determine, if Wnt3a-dependent production of IL-11 could contribute to profibrotic response we blocked IL-11 activity with anti-IL-11 neutralizing antibody in cardiac fibroblasts activated with TGF-β and Wnt3a. We found that neutralizing anti-IL11 antibody effectively suppressed production of αSMA, γSMA, fibronectin and pro-collagen I alpha 1, both on mRNA and protein levels. In line with these findings, blockade of IL-11 suppressed contractile properties of TGF-β/Wnt3a-activated cardiac fibroblasts. In conclusion, Wnt3a and Wnt5a differentially regulate gene expression of TGF-β-activated cardiac. Activation of the Wnt/β-catenin pathway promotes fibroblast-to-myofibroblast transition by enhancing production of profibrotic IL-11. It seems that identifying the profibrotic Wnt/β-catenin-IL11 mechanism in cardiac fibroblasts might represent a promising strategy in development of new therapies against cardiac fibrosis.

Abstract 100: Discovery of Cardiac Fibroblast Enriched microRNAs and Their Pivotal Roles in the Regulation of Cardiac Remodeling and Fibrosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yue Zhou ◽  
Arthur M Richards ◽  
Peipei Wang
Keyword(s):  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Cardiac Fibroblast ◽  
Tissue Growth ◽  
Functional Study ◽  
Coronary Artery Ligation ◽  
Alpha Smooth Muscle Actin ◽  
Artery Ligation ◽  
Rat Cardiomyocytes

Cardiac fibroblast (cFB) responses to cardiac injury or overload directly contribute to deterioration of cardiac function in heart failure. MicroRNAs (miR) target multiple genes in cell signaling networks and are likely to have pivotal regulatory roles with respect to cFB function. To date cFB enriched miRs have not been reported. We have identified cFB enriched miRs which we hypothesize direct cFB proliferation and differentiation. Neonatal and adult rat cardiomyocytes (CM) and cFBs were isolated and cultured. In vivo and in vitro cardiac ischemic models comprised coronary artery ligation induced myocardial infarction (MI) in rats and cultured cFB exposed to hypoxia. RNA and protein were extracted for miR microarray, qPCR and Western Blot. Adult cFB transfected with miR mimics were tested for CCK-8 proliferation assay. Fifteen dysregulated miRs were selected from array profiles and qPCR validation. Among them miR-31, -199a, -214 and -222 were highly expressed in adult cFBs 10-90 folds vs. CM. CM specific miR-208a and 133a were undetectable in cFB. Neonatal cells showed directionally concordant but less pronounced differences. In early MI, cardiac miR-31 was up-regulated >30 fold vs. Sham (infarct), others increased 6-12 folds. All changes were ranked infarct>border>remote area. As a control, non-cFB enriched miR-125a remained unchanged. Hypoxia treatment of cFB in vitro up-regulated miR-31 but not the other miRs. Functional study by mimic transfection revealed differential roles of the miRs. MiR-31 increased cFB proliferation in CCK8 assay. MiR-199a and -222 had opposite effects. MiR-199a, but not miR-222, reversed the pro-fibrotic effects of TGF-β. MiR-199a reduced mRNA and protein expression of alpha smooth muscle actin (α-SMA), a myoFB differentiation marker and connective tissue growth factor (CTGF), a predicted target (miRDB). Conversely miR-31 increased α-SMA and CTGF. We provide the first report of 4 cFB enriched miRs and demonstrated their pro- vs. anti-fibrotic roles in vitro (miR-31 vs. miR-199 and -222 respectively). In early MI, the increase of pro-fibrotic miR-31 was predominant, whilst other miR dysregulation was secondary to cFB proliferation. cFB enriched miRs determine cFB fate and progression of cardiac fibrosis/remodeling.

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