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• W2130606977 abstract "HomeCirculation: Heart FailureVol. 7, No. 1MicroRNAs in Heart Failure Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMicroRNAs in Heart FailureIs the Picture Becoming Less miRky? Yonathan F. Melman, MD, PhD, Ravi Shah, MD and Saumya Das, MD, PhD Yonathan F. MelmanYonathan F. Melman From the Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA (Y.F.M., S.D.); and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (R.S.). Search for more papers by this author , Ravi ShahRavi Shah From the Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA (Y.F.M., S.D.); and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (R.S.). Search for more papers by this author and Saumya DasSaumya Das From the Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA (Y.F.M., S.D.); and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (R.S.). Search for more papers by this author Originally published1 Jan 2014https://doi.org/10.1161/CIRCHEARTFAILURE.113.000266Circulation: Heart Failure. 2014;7:203–214Heart Failure: A Growing ProblemWith 550 000 new cases diagnosed annually and $37 billion spent per year,1 heart failure (HF) with reduced ejection fraction is one of the largest contributors to disease burden and healthcare expenditure in the United States. Despite significant progress in the treatment of HF2,3 with medications, the prognosis of HF remains dismal, with a mortality rate of 42% at 5 years after diagnosis. Therefore, understanding the underlying molecular pathways in the transition from established cardiovascular disease to HF may spur the development of novel biomarkers and therapeutic targets.The heart responds to stressors such as hypoxia (in myocardial infarction [MI]), increased wall stress (in valvular heart disease), and neurohormonal/metabolic stress (in diabetes mellitus and hypertension) by cardiomyocyte hypertrophy and fibrosis. Although initially compensatory for increased wall stress or myocyte loss, the molecular pathways that underlie pathological hypertrophy are ultimately maladaptive, recapitulating further hypertrophy, contractile dysfunction, apoptosis, and fibrosis. The progression to HF is associated with a characteristic cascade of altered intracellular signaling and gene expression, representing a final common pathway to ultimate decompensation. The various signaling pathways that underlie pathological hypertrophy and the progression to HF have been the subject of intense investigation and are summarized in multiple review publications.4–9. More recently, considerable attention has been paid to microRNAs (miRNAs), a novel biological control mechanism with the ability to regulate entire molecular networks by complex feedback and feed-forward mechanisms. Several reviews have summarized recent findings implicating miRNAs in cardiac development and disease.10,11 In the past few years, the discovery of circulating miRNAs has led to their investigation as biomarkers and mediators of cell–cell communication. This review focuses on recent developments detailing the role of miRNAs in the pathogenesis of HF, their potential role as biomarkers, and their use as possible novel therapeutic targets.microRNAs: Novel and Potent Regulators of Gene ExpressionThe first miRNA gene was identified in the worm Caenorhabditis elegans.12 In less than 2 decades, this initial finding has blossomed into an expanding field. miRNAs are now known to be fundamental regulators of post-transcriptional gene expression. Much light has now been shed on both the highly regulated synthesis of miRNAs and their mechanism of post-transcriptional gene silencing, the details of which are beyond the scope of this review (Figure 1).9,13,14Download figureDownload PowerPointFigure 1. Synthesis and mechanism of microRNAs (miRNAs): after synthesis of the primary RNA transcript (pri-miRNA), the molecule is processed by the endonucleases Pasha and Drosha to yield the pre-miRNA. After export to the cytoplasm the mature miRNA is generated by a cleavage step mediated by Dicer. The mature miRNA is then loaded onto the RNA-induced silencing complex (RISC). This complex can affect the degradation or translational repression of mRNAs harboring complementary sequences to the miRNA. Reprinted with permission from Mack.14 Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.miRNAs are initially transcribed as primary miRNAs (pri-miRNAs) and processed to precursor miRNAs (pre-miRNAs) by the RNase enzyme Drosha, which acts as part of a complex of regulatory and other proteins in the so-called microprocessor complex. The complex cleaves the initial pri-miRNA transcript at the stem of a hairpin loop to release a 60- to 70-bp molecule, the pre-miRNA. The pre-miRNAs are then transported to the cytoplasm in a highly regulated manner by proteins related to the exportin-5 family of Ran-GTPase–dependent proteins.15In the cytoplasm they undergo a further cleavage step by a complex containing Dicer to become mature double-stranded miRNAs,16 in most cases with 1 functional miRNA and a second complementary nonfunctional miRNA (in some cases, both miRNAs are functional and are designated by 5p and 3p based on their positions within the pre-miR). Subsequently, the mature miRNA is incorporated into a complex called the RNA silencing complex that contains the Argonaute protein.17 This complex, with the miRNA presented to the target mRNA, is responsible for repression of the target mRNA via either degradation of the mRNA or inhibition of translation. Watson–Crick complementarity between the seed region of the miRNA (nucleotides 2–8) and the complementary sequence in the 3'-untranslated region of the target mRNA seems to be 1 critical determinant of miRNA–mRNA interaction although other regions of the miRNA have now been shown to further influence this interaction (recently reviewed by Dorn10). In mammalian cells, mRNA translational repression rather than RNA-silencing seems to be the primary mode of miRNA action, and techniques to identify bona fide targets of miRNA are rapidly evolving10 (Figure 1).Large numbers of miRNAs have now been identified among all eukaryotic cells. Mirbase now lists >2000 known miRNAs in humans.9,18 Bioinformatics approaches to determining target mRNAs suggest that almost one third of all transcripts are miRNA targets, with single miRNA or members of a miRNA family regulating multiple components of pathways. A single miRNA may have tens to hundreds of targets in a given cell, and an individual mRNA may be targeted by multiple different miRNAs. Research to date has uncovered miRNAs in virtually all eukaryotic cells, and miRNAs have been implicated in biological processes ranging from embryogenesis to apoptosis, neoplasia to wound healing.The roles of individual miRNAs in cardiac development, HF, and hypertrophy have been studied extensively. Animal models have implicated multiple miRNAs in critical processes such as cardiac hypertrophy, fibrosis, and apoptosis. The intriguing discovery of miRNAs circulating in the plasma has spurred multiple recent studies assessing their potential use as prognostic biomarkers. In this review, we summarize our understanding of the role of these novel and important molecules in both the pathogenesis of HF and their emerging clinical role as diagnostic and predictive biomarkers.Involvement of MicroRNAs in Physiological and Pathological Adaptation: Hypertrophy, Fibrosis, and FailureAt the heart of maladaptive remodeling in response to mechanical and ischemic stress, the development and progression of pathological cellular and organ-level hypertrophy herald an inexorable decline in cardiac function before clinical HF. Reversing the process or slowing the transition to the decompensated state would be a major goal in treating the underlying pathological processes. A growing body of work has begun to shed light on the molecular mechanisms by which miRNAs affect pathological hypertrophy at the transition to HF. In this section, we discuss the evidence for the role of miRNAs as modulators of genetic networks responsible for pathological processes in HF progression, including hypertrophy, fibrosis, and apoptosis (see Figure 2 for important miRNAs involved in pathological and physiological cardiac remodeling).Download figureDownload PowerPointFigure 2. In response to pathological (pressure overload, ischemia–reperfusion), or physiological (exercise) stresses different microRNA (miRNA) expression patterns are observed. CsA indicates cyclosporin A; PE, phenylephrine; and TAC, transverse aortic constriction.Two knockout mice illustrate the importance of miRNA synthesis and regulation to cardiac function. The first, developed by Rao et al,19 was a knockout for a gene called dgcr8 that functions in conjunction with Dicer to generate pre-miRNAs from pri-miRNAs. Mice with a conditional, cardiac-selective knockout developed ventricular dysfunction by ≈3 weeks of life, followed by progressive ventricular dilatation and fibrosis. Mice with a dicer knockout developed a similar phenotype; although initially more ventricular hypertrophy was noted in these mice, the end result was a dilated, hypofunctional ventricle.20,21 Conditional, cardiac-specific deletion of Dicer in neural crest cells at various times in development and adulthood led to a shared phenotype of lethal cardiomyopathy.21A second line of investigation by van Rooij et al22 took the reverse process. miRNAs were measured in mice with pathological hypertrophy in response to either pressure-overload induced by transverse aortic constriction (TAC) or by constitutive calcineurin activation. Using a strategy of identifying miRNAs that were regulated in parallel in the TAC and calcineurin mice, the authors identified 11 miRNAs. At least 5 of these were upregulated in a similar manner in both mice and human cardiomyopathy tissue samples. Overexpression of these upregulated miRNAs (mir-23a, miR-23b, miR-24, miR-195, and miR-214) in primary cultured cardiomyocytes led to a dramatic hypertrophic response, whereas conversely, miRNAs that were downregulated in response to TAC or calcineurin (miR-150, miR-181b) led to a decrease in myocyte size suggesting a direct effect of these miRNAs on cardiac hypertrophy. The final proof of the causal role of miRNAs in cardiac hypertrophy was obtained using cardiac-specific overexpression of one of these miRNAs, miR-195 in transgenic mice, which led to cardiac hypertrophy because of marked cardiomyocyte enlargement. Interestingly, this hypertrophic response was followed by ventricular thinning, dilatation of the ventricular cavity, and deterioration of cardiac function. These studies demonstrated a functional role in the pathogenesis of HF in murine models for miRNAs implicated in human HF. An equally important conclusion from these early studies was that for some miRNAs, murine models of HF have relevance for developing mechanistic insight into human HF.Additional work by several groups has expanded our understanding of the role of individual miRNAs in cardiomyocyte hypertrophy (see Figure 3 for a brief list of genes and downstream targets)23 and in modulating response of the heart to physiological and pathological stresses.24–26 The number of miRNAs that are expressed in the heart seems to play a functional role in cardiac health and disease is growing rapidly (see Figure 2 for genes up- and downregulated in response to pathological and physiological stress by specific miRNAs). Although a complete description of all such molecules is beyond the scope of this review, we will instead focus on key miRNAs that play an important role in disease processes known to be important in the pathogenesis of HF.Download figureDownload PowerPointFigure 3. Multiple microRNAs (miRNAs) have been observed to modulate the hypertrophic process. Several of these are shown in the figure along with known mRNA targets. CTGF indicates connective tissue growth factor; ERK, extracellular signal-regulated kinase; IGF1, insulin-like growth factor 1; and IGFR, IGF receptor 1. Reprinted with permission from Nishimura et al.23 Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.miR Regulation of Cardiac HypertrophyMir-1: Regulation of Multiple Hypertrophy-Associated GenesMir-1 was first discovered in 200227 in a screen for muscle-specific miRNAs in mouse. In the mouse heart, 1 miRNA, mir-1 accounted for ≈40% of all miRNA transcripts in the cell. Zhao et al28 found that targeted deletion of mir-1 in mice led to the in utero death of 50% of the mice, and many of the remaining mice died of heart defects within a few months of birth. Sayed et al29 first demonstrated a role for miR-1 in cardiac hypertrophy, by subjecting mice to TAC (leading to pressure overload–induced hypertrophy). Comparison of miRNA expression profiles in sham and TAC-treated mice using a microarray approach that allowed for simultaneous screening of all 334 contemporary mouse miRNAs demonstrated a multitude of miRNAs that were either up or downregulated after TAC. miR-1 emerged as the predominantly expressed miRNA in cardiomyocytes, consistent with the data of Rao et al.19 In addition, it was downregulated early (1 day after TAC), and in a sustained manner for the 14-day duration of the study. The authors went on to show that miR-1 inhibited hypertrophy in neonatal mouse cardiomyocytes in response to serum-enriched media. Further work by several groups has identified several genes known to be involved in cardiac hypertrophy as downstream targets of miR-1.29–32Perhaps most compelling, Karakikes et al33 recently demonstrated that the adenoviral delivery of miR-1 to TAC-treated mice was able to reverse the hypertrophy and ventricular dysfunction–associated TAC, with improvement in fractional shortening, reversal of ventricular dilatation, and decreased fibrosis. On a gene expression level, a regression of the pathological hypertrophic profile was seen. In humans, Carè et al34 examined myocardial biopsies that were subjected to hypertrophic stimuli (atria in patients with mitral stenosis and myomectomy specimens from patients with hypertrophic cardiomyopathy undergoing surgical resection) and observed a decrease in miR-1 levels, suggesting a similar role in human hypertrophy. These studies suggested miR-1 as a plausible therapeutic target in HF, leading to further investigation of the pathways and mRNAs targeted by miR-1. Multiple studies have identified downstream targets of miR-1. In various studies, MEF2a, calmodulin, GATA4,30 insulin-like growth factor-1,31 and twinfillin32 have been shown to be downregulated by miR-1. All these molecules are known to be essential for the development of cardiac hypertrophy, providing a putative mechanism of miR-1 action.miR-133: the Most Abundant Human miRNAmiR-133 is the most abundant miRNA in human myocardium and was initially identified by microarray analysis as a muscle-specific miRNA.35 The 3 related miRNAs, miR-133a-1, miR-133a-2, and miR-133b, are cotranscribed with miR-1 to 2 and miR-1-1.36 miR-133 and miR-1 were initially reported to be downregulated in skeletal muscle after functional overload, suggesting a role in skeletal muscle hypertrophy and growth.35 Subsequently, several groups have confirmed the role of miR-133 in cardiac hypertrophy. Interestingly, a downregulation of miR-133 was noted34 in murine models of pathological TAC-induced hypertrophy or presumed physiological hypertrophy (constitutive Akt activation or exercise). The downregulation seemed to correlate with wall stress in the left ventricle (LV) in the TAC model. Inhibition of miR-133 using an adenovirus to express a complementary RNA to miR-133 (thereby sequestering the miRNA) in mice led to a process of hypertrophy and ventricular dilation; conversely, the overexpression of miR-133 was able to abrogate the hypertrophy induced by constitutive Akt activation, which has characteristics of both pathological and physiological hypertrophy. The investigators also showed downregulation of miR-133 in hypertrophied human ventricles. The molecules NFATc4 and calcineurin,35 both central regulators of cardiac hypertrophy, and Rac and Cdc42, 2 regulators of the prohypertrophic mitogen-activated protein (MAP) kinase pathways, have been identified as miR-133 targets.34,37Work by other groups suggests a more complex role for miR-133 in the regulation of cardiac hypertrophy. Although knockout of both 133a isoforms in the embryo is lethal because of heart defects,38 miR-133 overexpression in the developing heart driven by the β-myosin heavy chain (MHC) promoter did not seem to have any appreciable effects on LV function or dimensions. However, after TAC in the miR-133–overexpressing mice,39 the authors noted a significant decrease in myocardial fibrosis and improved ventricular compliance without appreciable cardiomyocyte hypertrophy. Interestingly, a different group40 demonstrated downregulation of miR-133 in both a rat model of hyper-reninemic hypertension (Ren2 rats) and humans with aortic stenosis, in concert with increased levels of connective tissue growth factor. The investigators demonstrated that miR-133 could directly downregulate connective tissue growth factor, suggesting a role for miR-133 both intramyocardially in regulating hypertrophy and potentially having paracrine downstream effects on the cardiac interstitium (perhaps by acting on fibroblasts). In sum, these studies suggest that downregulation of miR-133 may be deleterious in both cardiac development and hypertrophy, but that forced overexpression of this miR may be cardioprotective in certain models of pathological hypertrophy. These studies demonstrate the complex, context-dependent nature of miRNA regulation of cardiac phenotype: the role of the miRNA being investigated is often dependent on the exact model of hypertrophy and the nature of miRNA manipulation (eg, transgenic overexpression versus virally mediated gene delivery). Careful attention to these details is, therefore, necessary in elucidating a role for these miRNAs in cardiac disease.miR-208a: Regulation of MHC ExpressionmiR-208a is a cardiac-specific miRNA embedded within an intron of the α-MHC gene41 and hence is subject to the same transcriptional regulation as the α-MHC gene. A related miRNA, miR-208b, is encoded within the β-MHC genes. During embryogenesis, there is a switch from fetal β-MHC to α-MHC with a concurrent increase in the expression of miR-208a and reduction in miR-208b.42Interestingly, the overexpression of miR-208a leads to upregulation of β-MHC in mice and is sufficient to induce cardiac hypertrophy. The authors found that although the overexpressing mice had homogeneously increased expression of miR-208a in the heart, the areas of hypertrophied myocytes were restricted to certain focal areas, and these areas were surrounded by increased interstitial fibrosis. These results suggest that although miR-208a clearly mediates some aspects of hypertrophy, other cellular factors or conditions may be necessary for it to exert its downstream effects. miR-208a likely targets repressor proteins that may eventually contribute to β-MHC regulation43 with the thyroid hormone nuclear receptor (Thrap1) and myostatin being targets,42 but the exact mechanisms remain far from clear. Further, in cultured cardiomyocytes, transfection with miR-208a resulted in clear enlargement of the cells, and although knockdown of 208a with an antisense oligonucleotide resulted in diminished β-MHC levels, cell size was not affected at baseline, suggesting that miR-208a regulation of MHC is likely only 1 of many factors regulating cell size and hypertrophy.Nonetheless, these experiments led to the exploration of miR-208a as a possible target in pathological hypertrophy and HF. Indeed, genetic ablation of miR-208a in mice led to an absence of hypertrophic response to both TAC and calcineurin overexpression. In contrast to wild-type mice who undergo LV hypertrophy, with fibrosis and cardiomyocyte (CM) apoptosis after TAC, the miR-208a(−/−) mice displayed almost no increase in cardiac mass or LV size; as expected, there was no increased expression of β-MHC in response to TAC, but several other genes associated with hypertrophy (ANP [atrial natriuretic peptide], BNP [B-type natriuretic peptide]) were found to be increased, again suggesting that miR-208a may be a 1 of several key regulators of hypertrophy.42 Montgomery et al44 evaluated the role for of miR-208a in salt-sensitive hypertensive rats, which develop cardiac hypertrophy, fibrosis, and diastolic dysfunction in response to a high-salt diet. They found that inhibiting miR-208a blunted the increase in β-MHC in response to salt-induced hypertension, with concurrent amelioration of hypertrophy, intramyocardial fibrosis, and an improvement in diastolic function.Mir-378 Regulation of Hypertrophic SignalingmiR-378 is a muscle-enriched miRNA that is expressed in cardiomyocytes but not in fibroblasts. It was first identified in the heart as a miRNA that is expressed at significantly higher levels in 7-day-old neonatal mice compared with 16-day fetal hearts.45 miR-378 is expressed in both cardiac and skeletal muscle and was shown to directly downregulate expression of the insulin-like growth factor receptor 1 by binding to its mRNA. In neonatal cardiomyocytes, miR-378 overexpression leads to decreased insulin-like growth factor receptor 1 and inhibition of its downstream effectors PI-3K (phosphatidylinositol 3-kinase) and Akt.45 These are important antiapoptotic signals under conditions of stress, and in fact inhibiting miR-378 was cardioprotective against apoptosis in response to hydrogen peroxide or hypoxic stress.In contrast, there was a decrease in miR-378 in the heart after TAC, and maintenance of miR-378 levels by genetic overexpression of miR-378 decreased hypertrophy and improved LV function.46 The authors found miR-378 levels to be decreased in both a mouse TAC model and in a β1-adrenergic receptor overexpression model, as well as in human patients with dilated cardiomyopathy, and that miR-378 directly suppresses insulin-like growth factor receptor 1, Ksr1, Grb2, and MAP kinase 1, all components of the MAP kinase signaling cascade known to be involved in cardiac hypertrophy. A second group working similarly identified miR-378 as a negative regulator of hypertrophy in mouse TAC and isoproterenol infusion models, as well as in a rat aorto-caval volume overload model in addition to human dilated cardiomyopathy hearts. The authors identified and confirmed by luciferase assay that Grb2 was a target of miR-378.46,47 These experiments again underlined a recurrent theme in miRNA biology, namely that the role of the miRNA seemed to be specific to the type of disease model and type of stressor investigated and cautioned against generalization of results obtained from any particular model.miRNA Regulation of FibrosismiR-29: Regulation of Profibrotic GenesmiR-29 was identified by a microarray screen looking at miRNA species that are differentially regulated in a rat model of MI.48 miR-29 was noted to be dramatically downregulated in the border zone of an induced left anterior descending territory infarction compared with noninfarcted myocardium from the same heart. These findings were reproduced in explanted human hearts at the time of transplantation, where levels of miR-29 were significantly lower in the border zones of hearts that had suffered MIs relative to nonfailing hearts. The investigators demonstrated that miR-29 targeted genes involved in cardiac remodeling and fibrosis, including elastin, fibrillin 1, collagens type I and III. miR-29 seemed to be downregulated by transforming growth factor-β, a regulator of cardiac fibrosis.48 In an interesting study, Zhou et al49 implicated miR-29 in myoblast transdifferentiation into myofibroblasts in vitro, consistent with its role as a mediator of tissue fibrosis. In the mdx mouse model of Duchenne muscular dystrophy, the skeletal and cardiac muscles are gradually replaced by fibrotic tissue in a manner paralleling the human disease. miR-29 levels are decreased in mdx myoblasts and restoration of miR-29 levels inhibited this fibrotic process by inhibiting myoblast transdifferentiation.50The role and regulation of miR-29 are emerging as both crucial to the regulation of cardiac fibrosis and to cardiac adaptation to a variety of stimuli. During exercise training of Wistar rats, downregulation of the antihypertrophic miRNAs, miR-1, miR-133a, and miR-133b, was observed with concurrent upregulation of miR-29 and downregulation of its known target connective tissue mRNAs. The authors hypothesized that upregulation of miR-29 may underlie the improved diastolic function seen with exercise training although this is yet to be proven by manipulation (overexpression or inhibition) of miR-29 levels.51These experiments suggested that miR-29 is a central regulator of cardiac fibrosis and may play an important role in LV remodeling after stressors. In the heart under normal conditions, the fibrotic process itself can be both adaptive and maladaptive. After MI the transdifferentiation and matrix-synthetic pathways are essential for the rapid formation of a protective fibrotic scar to replace ischemic, necrotic myocardium; however, the overproduction of fibrotic tissue in the heart can lead to diastolic and systolic dysfunction and adverse hemodynamic consequences. Future manipulation of miR-29 may need to take into account these complex dynamics. The upregulation of miR-29 under exercise conditions thus represents a favorable adaptation that improves hemodynamics under high cardiac workloads, but whether upregulation of miR-29 after MI is beneficial needs to be established.miR-21: Regulation of MAP kinase Profibrotic SignalingRoy et al52 first described miR-21 as a miRNA increased in mouse hearts subjected to ischemia–reperfusion in the infarct zone. Using laser microdissection they were able to show that the upregulation was restricted to infarcted and reperfused myocardium and not to surrounding tissues. In situ hybridization demonstrated that miR-21 expression was restricted to fibroblasts in the infarct zone. The authors went on to demonstrate that miR-21 is a direct inhibitor of PTEN (phosphatase and tensin homolog; a phosphatase that dephosphorylates PIP2 [phosphatidylinositol 4,5-biphosphate]), thereby leading to akt activation and production of the matrix metalloproteinase MMP-2 in fibroblasts.Contemporaneously, miR-21 was also shown to be upregulated in microarray screen in a β-adrenergic receptor transgenic mouse model of HF. Thum et al53 demonstrated that miR-21 levels were increased selectively in fibroblasts of failing mouse hearts. The authors showed that Sprouty2 was a target of miR-21 in cardiac fibroblasts, and that inhibition of Sprouty2 led to extracellular signal-regulated kinase (ERK)1/2 activation. The consequence of this was decreased fibroblast apoptosis and increased FGF (fibroblast growth factor) secretion, suggesting that miR-21 led to a profibrotic program in the heart. Importantly, inhibition of miR-21 by an antagomir protected mice subjected to TAC from fibrosis, hypertrophy, and LV dilatation. Relevance to human heart disease was provided subsequently on examination of plasma and biopsy samples in 75 patients with aortic stenosis.54 Levels of miR-21 were increased in patients with aortic stenosis, but decreased after surgical correction of the valvular disease, and importantly, the level of miR-21 correlated with myocardial collagen level. Consistent with findings of prior groups, miR-21 expression was restricted to interstitial cells in the biopsy samples.Whether miR-21 also plays a role in cardiomyocyte biology remains unclear. Although the overexpression did not induce hypertrophy,53 Sayed et al55 found that overexpression of miR-21 in neonatal CMs led to Sprouty2 suppression and induced slender outgrowths that promote cell-to-cell connection and gap junction formation. Whether this has any relevance to in vivo models or is an artifact of viral overexpression in a cell type where the miRNA is not usually expressed (thereby leading to off-target effects) has not been fully explored.miR-24: Regulation of Cardiomyocyte and Fibroblast FunctionmiR-24 was originally identified as a miRNA species that was differentially regulated after TAC in mice22 and was shown to be downregulated in a murine model of MI.56 Suppression of miR-24 was maximal 1 week after infarction, with levels returning to normal by 2 weeks after infarction. The authors observed concurrent upregulation of collagen, transforming growth factor-β, and fibronectin. Mice with adenoviral-driven miR-24 expression (via direct adenovirus injection into myocardium) before infarction induced by left anterior descending ligation exhibited significantly reduced infarct scar size. The effects of miR-24 seemed to be mediated by inhibition of fibroblast proliferation. The authors identified the protease furin as a miR-24 target by bioinformatics analysis and showed that inhibition of furin was sufficient to inhibit downstream transforming growth factor-β signaling.56The role of miR-24 in cardiomyocytes was elucidated in a different study, which identified the protein junctophillin-2 as a putative miR-24 target. Junctophillin-2 is a protein involved in structurally" @default.
• W2130606977 created "2016-06-24" @default.
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• W2130606977 date "2014-01-01" @default.
• W2130606977 modified "2023-10-14" @default.
• W2130606977 title "MicroRNAs in Heart Failure" @default.
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