ABC | Volume 111, Nº5, November 2018

Review Article Silva et al miRNAs and cardiovascular disease Arq Bras Cardiol. 2018; 111(5):738-746 Figure 3 – Cardiac remodeling and miRNAs. Main miRNAs that modulate cardiac hypertrophy and tissue fibrosis during adverse cardiac remodeling in many diseases are here illustrated. MiR-1, -133a, -208a/b and -499 are believed to be specific for cardiac tissue, as they are more abundant in this tissue than in others. These miRNAs are involved in mesodermal precursor differentiation, in transdifferentiation/ reprogramming of adult fibroblasts/myofibroblasts into mature cardiomyocytes, and preservation of normal function and survival of cardiomyocytes. 40 In pathologic conditions, dysregulation of cardiac miRNAs may lead to HF progression, combined with arrhythmia, ischemia, ventricular dilatation, fibrosis and tissue necrosis. Cardiomyocytes MiR-1 is one of the most abundant miRNAs, responsible for the control of different aspects of differentiation and proliferation of cardiomyocytes. In animals, miR-1 would be involved in the proliferation and differentiation of cardiac cells during cardiogenesis. 41 However, increased expression of miR-1 can cause arrythmia, as it controls cardiac conductance and automaticity by modulating the expression of proteins involved in intracellular calcium regulation. 42 MiR-21 is predominantly expressed in cardiac fibroblasts. Its increased expression was shown to indirectly promote cardiac hypertrophy by stimulating Mitogen Activated Protein (MAP) kinases in an animal model of HF, 43 although there is evidence that increased expression of miR-1 has an anti‑hypertrophic role in isolated cardiomyocytes. 44 Silencing of miR-208 in an animal model of AMI attenuated apoptosis, hypertrophy and fibrosis, promoting improvement in cardiac function. 45 There is evidence that miR-133 protects cardiomyocytes from hypertrophy in neonatal rats. Mechanisms involved in this process include modulation of intracellular calcium concentrations and reduction of mRNA expression into ANP and myosin heavy chain beta MHC- β . 46,47 MiR-223 could suppress hypertrophy by decreasing calcium intracellular concentrations, cardiomyocyte contractility, and phosphorylation of cardiac troponin I (cTNI). 4 MiR-124 would be involved in cardiac hypertrophy, since its expression is increased in a model of angiotensin II-induced hypertrophy in primary cultured rat neonatal cardiomyocytes, and inhibition of its expression would suppress angiotensin II-induced hypertrophy. 49 In mice, induction of miR-499 expression in the heart caused cellular hypertrophy and cardiac dysfunction due to altered expression of contractile proteins – MYH7B and skeletal muscle actin alpha 1 (ACTA1). 50 Fibrosis Connective tissue growth factor (CTGF) is considered a key molecule in the fibrotic process, as it induces the synthesis of extracellular matrix (ECM). Duisters et al. 51 demonstrated that miR-133 and miR-30 regulate CTGF expression. 51 CTGF expression is inversely proportional to the expression of these miRNAs in models of cardiac diseases in rodents (genetic model with hyperactivation of the renin-angiotensin-aldosterone system, cardiac hypertrophy and HF) and in disease-related left ventricular remodeling in biopsy samples of patients with aortic stenosis undergoing valve replacement surgery. Besides, increased expression of miR-133 and miR‑30 reduces CTGF expression, resulting in decreased collagen deposition. 51 On the other hand, miR-203 may play a pro‑fibrogenic role, since induction of its expression in cultured mouse cardiomyocytes increases the synthesis of CTGF, transforming growth factor beta 1 (TGF- β 1) and fibronectin. 52 Mir-29 also seems to play an important role in ECM remodeling in patients with HF. Mir-29 is preferentially expressed in fibroblasts, in areas surrounding infarcted areas. It would be involved in apoptosis, specially at final stages of HF, reducing collagen expression. 53 In an animal model of infarction, miR-24 expression is reduced, which is correlated with EMC remodeling. MiR-24 expression induced by synthetic precursors inhibits fibrosis, and differentiation and migration of cardiac fibroblasts. 21 MiR-98 seems to have a similar mechanism, since induction of its expression in human cardiac fibroblasts inhibits TGF- β 1-induced fibrosis. 54 741