|Year : 2016 | Volume
| Issue : 2 | Page : 79-85
Epigenetic role of micrornas in diabetic cardiomyopathy
Satish K Raut, Akhilesh Kumar, Madhu Khullar
Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||7-Oct-2016|
Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012, India
Source of Support: None, Conflict of Interest: None
Cardiovascular complications in diabetic individuals account for significant morbidity and mortality. Clinical and epidemiological studies have also shown significantly increased incidence and prevalence of cardiovascular complications in diabetes. Heart failure (HF) in diabetes in the absence of known cardiac complications such as myocardial infarction and coronary artery disease further supports the existence of diabetic cardiomyopathy (DbCM). Myocyte hypertrophy and myocardial fibrosis are the established pathological features of the DbCM and are associated with differential expression of genes involved in cardiac hypertrophy and fibrosis. Recent studies show the role of tiny noncoding regulatory RNAs, known as microRNAs (miRs), in the transcriptional and post-transcriptional regulation of gene expression. A large number of miRs have been identified that regulate diverse aspects of cardiac development and function and also play key role in regulating various signaling pathways involved in the pathogenesis of HF. The present review provides an overview of the role of miRs in diabetes-associated heart disease.
Keywords: Diabetes, diabetic cardiomyopathy, microRNA
|How to cite this article:|
Raut SK, Kumar A, Khullar M. Epigenetic role of micrornas in diabetic cardiomyopathy. J Pract Cardiovasc Sci 2016;2:79-85
| Introduction|| |
The epidemic of diabetes is alarming in both developing and industrialized world, and it has been estimated that by the year 2025, 300 million people will be affected by the disease.,, Among the vast array of vascular complications associated with diabetes, cardiovascular complications significantly contribute to morbidity and mortality. Nearly, 80% of the deaths associated with diabetes are reported to be due to cardiac complications. The Framingham study demonstrated several folds increased the incidence of congestive heart failure (HF) in diabetic males (2.4:1) and females (5:1), independent of age, hypertension, obesity, coronary artery disease (CAD), and hyperlipidemia., Other prospective studies also show that diabetic patients have a significantly increased lifetime risk of developing HF., Although the previous studies have focused on CAD and autonomic neuropathy as the primary cardiac complication, over the last 30 years, diabetic cardiomyopathy (DbCM) has been identified as a significant entity.
Epidemiological, clinical, and experimental studies have shown that diabetes results in functional and structural changes in the myocardium which are independent of hypertension, CAD, or any other known cardiac disease supporting the existence of DbCM.,, DbCM is characterized functionally by myocyte loss, myocardial fibrosis, and left ventricular hypertrophy leading to decreased elasticity and impaired contractile function. It is associated with diastolic or systolic dysfunction or a combination of both.,,
The pathophysiology of DbCM is incompletely understood but appears to be initiated both by hyperglycemia and changes in cardiac metabolism.,, The pathogenesis of DbCM is multifactorial, and several hypotheses have been proposed including metabolic derangements, abnormalities in ion homeostasis, alteration in structural proteins, oxidative stress, inflammation, and endothelial dysfunction. Recent studies have revealed that dysregulated expression of several pathway-specific genes may significantly contribute to these processes.,,
Gene expression is the process by which the DNA sequence or gene is transcribed into microRNA (miR) which further translated into protein. Each cell of a multicellular organism contains the same set of genes, yet each with a distinctive pattern of gene expression. Control of gene expression in eukaryotic cells is known to occur at several levels, including chromatin structure, transcriptional initiation, transcript processing, transcript stability, translational initiation, posttranslational modification, and protein stability. However, the recent discovery of the existence of miRs has introduced an additional mechanism of control of gene expression, where miRs repress protein expression of target miRs by miR degradation or translational repression.
| Micrornas|| |
MiRs are a novel class of small noncoding single-stranded gene regulatory RNAs of approximately ~22 nucleotides. In mammals, the majority of miRs are located within introns of either protein-coding or noncoding host genes, while others, depending on the occurrence of alternative splicing, are present either in an exon or an intron. A significant number of miRs are also assembled in clusters in which two or three miRs are generated from a common parent miR. MiRs are estimated to comprise at least 1% of animal genes and regulate 30% of the human genome, i.e., each miR regulate the expression of more than one target gene making them one of the most abundant classes of regulators with a pattern of expression that is often perturbed in disease states.,,, Cell- and tissue-specific expressions are an important feature of miR expression. A specific expression pattern can be imposed by host genes when miRs are located in their respective introns. Indeed, one miR may be dominantly expressed in some tissue but may have no or low expression in other tissues.
Heart expresses a large number of miRs, in general, housekeeping miRs maintain essential cellular functions, homeostatic miRs sustain normal heart-specific functions, and stress-responsive miRs reprogram the heart under conditions of injury or overload. Thus, stress-responsive miRs extract information from the environment and implement stimulus-specific transcriptional and posttranslational changes in the heart, leading to physiological and pathological changes in the heart. Increasing evidence supports that miRs play indispensable role in the pathophysiology of cardiovascular diseases such as arrhythmia, cardiac hypertrophy, and HF.,,
| Micrornas and Diabetic Cardiomyopathy|| |
Myocardial fibrosis and hypertrophy are established pathological feature of DbCM which significantly contributes to diabetes-associated HF.,, Cardiac fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) proteins resulting in impaired ventricular function and predisposing the heart to arrhythmias. Diffused myocardial fibrosis, extensive necrosis, and replacement of contractile myofibers by fibrotic tissue are commonly seen in DbCM. Myocardial hypertrophy functionally manifests as defective cardiac contractility and is characterized by an increase in cardiomyocyte size, protein synthesis, and changes in the organization of sarcomeric structures. However, the molecular mechanisms that lead to myocardial fibrosis and hypertrophy in diabetes are not well elucidated.
Recent studies have shown a central role for miRs in the etiology of cardiac fibrosis, as well as in myocardial hypertrophy. The first evidence for the role of miRs in cardiac fibrosis came from the study by da Costa Martins et al., who showed that deletion of Dicer, an enzyme involved in the biogenesis of miRs, in the mouse myocardium resulted in cardiomyocyte hypertrophy and extensive myocardial fibrosis. A distinct and differential expression of miRs has been observed in cardiac remodeling in human and murine hearts.,,,,,, Functional significance of miRs in cardiac biology has been validated by gain and loss of function studies. The aim of this review is to describe the role of miRs in DbCM, with reference to differential expression of miRs involved in diabetes/hyperglycemia-induced myocardial fibrosis and myocardial hypertrophy. Specifically, we have looked at their role in regulating the expression of genes known to be involved in the pathophysiology of DbCM. We performed literature search with keywords DbCM, hyperglycemia, cardiac fibrosis, cardiac hypertrophy, and miRs using various online search tool and found research on the role of miRs in DbCM is at very nascent stage. In the present review, we discuss miRs whose expression, as well as function, has been validated in diabetic and HF.
MiR-1 is a muscle-specific miR and is most abundantly expressed in heart. MiR-206 is an another miR, which is paralogs to miR-1., It is specifically expressed in cardiac precursor cells, and its target gene is a direct transcriptional target of muscle differentiation regulators, including serum response factors (SRFs), myogenic differentiation factor D, and myocyte-enhancing factor-2 (MEF2).
MiR-1 has been proposed to play an important role in the pathophysiology of cardiac hypertrophy, myocardial infarction, and arrhythmias., Recent publications have shown that hyperglycemia resulted in increased miR-21 expression in cardiomyocytes , and endothelial cells, which has a further significant role in triggering diabetes-induced HF. In 2008, Yu et al. reported increased miR-1 expression in rat cardiomyocytes (H9C2) exposed to high glucose. They observed that H9C2 cells exposed to high glucose (25 mM) for 72 h had 4-fold increased miR-1 expression and decrease in mitochondrial membrane potential (Δψ) with an increase in cytochrome-c release and increased apoptosis. Glucose-induced mitochondrial dysfunction, cytochrome-c release, and apoptosis were blocked by insulin-like growth factor-1 (IGF-1). Using prediction algorithms, they identified 3'-untranslated regions of IGF-1 gene as the target of miR-1. They observed that miR-1 mimics prevent glucose-induced mitochondrial dysfunction, cytochrome-c release, and apoptosis through IGF-1. They concluded that hyperglycemia-induced increased apoptosis of cardiomyocytes was mediated IGF-1 signaling pathway regulated by miR-1. Recently, Shan et al. also showed that increased levels of miR-1 and miR-206 in the hearts of streptozotocin (STZ)-induced diabetic Sprague-Dawley (SD) rats in neonatal ventricular cardiomyocytes and in H9c2 cells exposed to high glucose. They reported a time-dependent increased cardiomyocytes apoptosis in the diabetic myocardium in STZ-induced SD rats. SRF is transcriptional factor shown to regulate miR-1 expression during cardiogenesis. SRF has been found to be upregulated in cardiomyocytes exposed to high glucose and shown to modulate miR-1 and miR-206 expression. MiR-1 and miR-206 share an identical seed sequence and bind to the same site in the 3'-UTR of Hsp60 miR and thereby could regulate Hsp60 expression and glucose-mediated apoptosis in diabetic myocardium, however, this needs experimental validation.
These studies have shown that miR-1 is an important mediator of gene regulation during HF induced by various stress including high glucose. However, its therapeutic potential has not yet been elucidated.
MiR-21 is one of the highly conserved and universally expressed mammalians miR identified. Human miR-21 gene is located in chromosome 17, whereas in rat and mouse miR-21 gene is at chromosome 10 and chromosome 21, respectively.
MiR-21 has been implicated in various human diseases including cardiovascular diseases. It is expressed in vascular smooth muscle cell, endothelial cell, cardiomyocytes, and cardiac fibroblasts. Data from the various studies based on differential expression of miR showed miR-21 are the most common miR found to be differentially expressed in different rodent models of HF such as transverse aortic constriction, β-1-adrenergic receptor transgenic mice, isoproterenol, and also in human patients of HF such as myocardial ischemia, idiopathic cardiomyopathy, and dilated cardiomyopathy (DCM).,,,,,,,, However, the change in miR-21 expression in various human heart diseases is inconsistent. For example, it was shown to be upregulated in cardiac fibroblasts after ischemic reperfusion injury and downregulated in infarcted areas in a mouse model of acute myocardial infarction. Thum et al., 2008, recently showed that miR-21 was upregulated selectively in fibroblasts of the pressure-overloaded heart but not in cardiomyocytes. Similarly, Liu et al. also showed that high glucose treatment results in increased miR-21 expression in cardiac fibroblasts.
The altered miR-21 has been proposed to mediate cardiac hypertrophy and cardiac fibrosis under different forms of cardiac stress; however, its functional characterization and role on cardiac hypertrophy and fibrosis in the diabetic heart are not well elucidated. Preliminary work of our laboratory showed an increased expression of miR-21 in STZ-induced Wistar rat model of DbCM and also in high glucose-treated cardiac fibroblasts. We also found an increased expression of miR-21 in formalin-fixed paraffin-embedded (FFPE) archival tissue of human patients of DbCM [Figure 1]. The increased miR-21 expression activates Akt/protein kinase B (PKB) signaling in DbCM and hyperglycemic (HG)-treated cardiac fibroblasts and hence involved in cardiac fibrosis in DbCM. We also observed that in vitro reduction of miR-21 levels in cardiac fibroblasts attenuated cardiac fibrosis through the downregulation of HG-induced increased fibrotic genes expression (Col-1a, Col-3a, Col-4a, transforming growth factor-β, and connective tissue growth factor [CTGF]), myofibroblasts differentiation, and cardiac fibroblasts proliferation.
|Figure 1: (a) Real-time polymerase chain reaction analysis showed a decreased miR-30c expression in the heart of diabetic rats (n = 6/group), archived myocardial tissue of patients with dilated cardiomyopathy (n = 5/group) and H9c2 cardiomyocytes exposed to 30 mM D-glucose as compared to normal glucose (b) real-time polymerase chain reaction analysis showed an increased miR-21 expression in the heart of diabetic rats (n = 6/group), archived myocardial tissue of patients with dilated cardiomyopathy (n = 5/group), and fibroblast exposed to 30 mM D-glucose as compared to normal glucose at 48 and 72 h.|
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MiR-21 has been recently reported to regulate the genes involved in cardiac fibrosis. For example, the overexpression of miR-21 was shown to increase fibroblast survival resulting in fibrosis by downregulating SPRY1, a potent inhibitor of the Ras/MEK/ERK pathway. This study has also suggested that silencing of miR-21 expression using synthetic oligos in a mouse model of HF resulted in reduced interstitial fibrosis and attenuated cardiac dysfunction, suggesting the potential role of miR-21 in cardiac fibrosis associated with DbCM.
Similarly, miR-21 has been also shown to increase the expression of matrix metalloprotease-2 by downregulating phosphatase and tensin homolog (PTEN) expression in cardiac fibroblasts in response to ischemia/reperfusion (I/R) in the mouse hearts, suggesting that miR-21 may contribute to the modulation of cardiac fibrosis in ischemic injury. PTEN is a negative regulator of Akt-PKB pathway. Akt/PKB signaling pathway is a cell survival pathway and involved in ECM synthesis myofibroblasts differentiation and cell proliferation as a hallmark of cardiac fibrosis.,,,,, A recent study has reported that hyperglycemia is a potent inducer of activation of Akt/PKB signaling pathway; thereby may be involved in tissue fibrosis and cell proliferation during DbCM. Recently, Liu et al. have shown that in DbCM, high glucose-induced the proliferation and collagen synthesis in cardiac fibroblasts along with increased miR-21 expression. Further, gain and loss of miR-21 function confirmed that miR-21 negatively regulates DUSP8 expression and enhanced cell proliferation and collagen synthesis through p38 and c-Jun N-terminal kinase/stress-activated kinase signaling.
In summary, results from both basic and clinical studies suggest that miR-21 plays an important role in diverse cardiovascular diseases. Although miR-21 is differentially expressed in diabetic myocardium and regulates expression of several pathological pathways common to DbCM; however, its role in DbCM is not yet fully elucidated.
MiR-30 family is made up of five members, named miR-30a-30e, having 100% conservation in seed sequence homology. The miR-30 family has been studied extensively to identify the precise mechanisms of Drosha activity as well as the sequence requirements for miR biogenesis and function., The miR-30 family is known to regulate various biological processes, including pancreatic islet cell development, mitochondrial fission, adipogenesis, and osteoblast differentiation. However, its role in physiological or pathological mechanisms in the heart is not much explored. Duisters et al. were the first to report that CTGF as a target gene for miR-30. They also reported that miR-30 knockdown resulted in increased CTGF expression in both cardiomyocytes and cardiac fibrosis and hence involved in cardiac hypertrophy and fibrosis.
Raut et al. recently showed that miR-30c expression was decreased in DbCM rats, FFPE human myocardial archived tissue from patients with DbCM, and in HG-treated cardiomyocytes [Figure 1]. We also found that overexpression of miR-30c resulted in decreased Cdc42 and Pak1 genes and attenuated HG-induced cardiomyocyte hypertrophy, whereas a decrease in miR-30c levels resulted in increased Cdc42 and Pak1 gene expression leading to myocyte hypertrophy in HG-treated cardiomyocytes, in vitro. These results suggested the pro-hypertrophic potential of miR-30c in DbCM through the regulation of Cdc42 and Pak1 genes.
MiR-133 is recognized as myomiR which regulates cardiac and skeletal muscle differentiation and has been proposed to mediate cardiac hypertrophy under different forms of cardiac stress., In the human genome, miR-133 encodes three genes: miR-133a-1, miR-133a-2, and miR-133b detected on chromosomes 18, 20, and 6, respectively. Xiao et al. showed an increased miR-133 expression in alloxan-induced diabetic rat heart suggesting its role in cardiac dysfunction. In this study, authors have shown that increased miR-133 expression was associated with downregulated electroretinogram channel expression, leading to arrhythmia in diabetic heart suggesting the similar mechanism may be operating in DbCM. MiR-133 has also shown to be significantly involved in both cardiac hypertrophy and fibrosis as an important pathological feature of DbCM. MiR-133 was shown to be a modulating the expression of genes involved in cardiac hypertrophy, such as RhoA, a GDP-GTP exchange protein; Cdc42, a signal transduction kinase; calcineurin, and Nelf-A/WHSC2, a nuclear factor (NF). RhoA and its downstream target Rho kinase (Rho-associated coiled-coil protein kinase or ROCK) are variously involved in cell contraction and modulation of actin cytoskeletal assembly and thereby involved in myocyte hypertrophy. Dong et al. have suggested that apart from Nfatc4, calcineurin is a direct target of miR-133 and has shown in hypertrophic heart, increased calcineurin expression in association with decreased miR-133 expression, and found increased miR-133 expression with the inhibition of calcineurin, protects against cardiac hypertrophy.
MiR-133, along with miR-30c, has been suggested to play an important role in the control of myocardial matrix remodeling by targeting the CTGF, a profibrotic protein involved in cardiac remodeling during both myocytes hypertrophy and cardiac fibrosis. Overexpression of miR-133 was found to reduce the expression of its target gene Krüppel-like factor 15 (KLF15) and downstream target Glucose transporter type 4, (GLUT4) indicating that miR-133 regulates the expression KLF15 and GLUT4 which is involved in metabolic control in cardiac myocytes. An impaired regulation of miR-1 and miR-133a by insulin in the skeletal muscle of type 2 diabetic patients was suggested to be consequences of altered SREBP-1c activation.In vitro exposure to hyperglycemia decreased the expression of miR-133a and resulted in hypertrophic changes in cardiomyocytes and augmented the gene expression of MEF2A, MEF2C, SGK1, and IGF receptor-1 (IGF-1R).
In summary, miR-133 may introduce new prospects for the management in the field of DbCM.
During diabetes, miR-221 is known to be involved in endothelial cell migration and proliferation. However, miR-221 has also known to be involved in cardiac hypertrophy, but its role in DbCM is not yet studied. Recent data have suggested that miR-221 has some antihypertrophic and antiangiogenic function. For example, miR-221 was shown to be downregulated in transverse aortic constricted mice model of cardiac hypertrophy. However, another report has shown that miR-221 expression was increased in both transverse aortic constricted mice and patients with hypertrophic cardiomyopathy. In the same study, authors have shown that overexpression of miR-221 in isolated cardiomyocytes was found to increase their cell size and induced the re-expression of fetal genes, which could be inhibited by inhibition of endogenous miR-221. These effects of miR-221 were mediated by downregulation of p27. Similarly, miR-221 has also been proposed to contribute to endothelial dysfunction in diabetes. Decreased expression of miR-221 has been observed in human umbilical vein endothelial cells (HUVECs) treated with high glucose concentrations. Downregulation of miR-221 was found to trigger the inhibition of c-kit and impaired HUVECs migration. In general, c-Kit tyrosine receptor kinase, a well-established stem cell marker and involved in cardiomyocytes regeneration  and it is also involved in regulation of glucose metabolism and plays an important role in beta-cell development and function. However, modulation of miR-221 in HUVECs may offer a novel strategy for treatment for diabetic patients with vascular dysfunction and a potential intervention target for cardiac hypertrophy in HF.
MiR-320 family has includes miR-320a, miR-320b-1, miR-320b-2, miR-320c-1, miR-320c-2 and miR-320d-1, miR-320d-2, miR-320e. The previous study has shown that decreased miR-320 expression in plasma samples of the prospective population-based Bruneck study, whereas reverse transcription-polymerase chain reaction analysis showed increased miR-320 expression in myocardial microvascular endothelial cells (MMVECs). This increased miR-320 expression resulted in decreased IGF-1 and IGF-1R and thereby leading to impaired angiogenesis. Authors also showed that transfection with miR-320 inhibitor in diabetic MMVEC improved proliferation and migration of these cells. In diabetic rat heart, cardiomyocytes mediated its antiangiogenic function through the exosomal transfer of miR-320 into endothelial cells. Ren et al. reported decreased miR-320 expression in murine hearts during I/R. Transgenic mice with cardiac-specific overexpression of miR-320 showed an increased apoptosis and infarction size in the hearts on I/R.In vitro gain of function of miR-320 enhanced cardiomyocyte apoptosis, whereas knockdown was beneficial on simulated I/R. These studies suggested a role of miR 320 in cardiac pathophysiological processes. In summary, it appears that miR-320 may have a role DbCM but further studies are needed to identify its target pathways/mechanisms in the diabetic heart.
| Micrornas Involved in Diabetic Metabolism|| |
Several miRs have been also found to be differentially expressed in organs other than heart, regulating various signaling pathways involved in diabetes and associated complications, such as glucose and lipid metabolism, glucose transport, and insulin signaling. Similar/these miRs were also found to be differentially expressed in the heart but have not been functionally characterized in the diabetic myocardium. On the basis of similar target genes involved in various signaling pathways of myocardium metabolism in diabetes, we may speculate that these miRs may also regulate the same targets gene and thereby signaling pathways such as glucose and lipid metabolism, glucose transport, and insulin signaling in DbCM.
MiR-375 is one of such miR and abundantly present in islet cells of the pancreas. Overexpression of miR-375 in pancreatic-β cells during diabetes negatively regulates glucose-stimulated insulin secretion (GSIS) through downregulation of myotrophin (Mtpn) expression, a protein involved in insulin – granule fusion. Indeed, myotrophin is a well-known transcriptional activator of NF-kappa B (NF-κB) in cardiomyocytes, suggesting that the regulation of myotrophin by miR-375 may lead to alteration in NF-κB activity in cardiomyocytes and thereby regulates myocytes hypertrophy.
MiR-375 also negatively regulates the expression of phosphoinositide-dependent protein kinase-1, a key component of PI3-kinase signaling cascade, thus leading to decreased insulin-stimulated phosphorylation of Akt and glycogen synthase kinase 3. PI3K-Akt is a well-studied pathway in cardiomyocytes and promotes cardiomyocytes survival during various heart injuries. However, apart from regulating various important pathways, the role of mir-375 has not been yet studied in the diabetic heart but in one of the reports, mir-375 expression was found to be decreased by 50-fold in plasma during myocardial infarction.
In the heart, miR-30d and miR-15a were other miRs found to be differentially expressed in the heart during DCM and ischemic cardiomyopathy. MiR-30d overexpression increased insulin gene expression in MIN6 cells (pancreatic-β cell line), whereas its inhibition attenuated glucose-stimulated insulin gene transcription. Whereas, miR-15a promoted insulin biosynthesis in mouse pancreatic-β cells by inhibiting endogenous UCP-2 (uncoupling protein-2) expression, an inhibitor of GSIS. During diabetes, reactive oxygen species activates UCP2, which inhibits GSIS by uncoupling oxidative phosphorylation.
In diabetic myocardium, miR-29 family was also found to be upregulated and regulates insulin-induced genes-1 in 3T3-L1 adipocytes and decreased Akt phosphorylation suggesting the potential role of miR-29 family in insulin resistance.
More recently, miR-27b and miR-130 overexpression impaired adipogenesis by targeting peroxisome proliferator-activated receptor expression, the receptor target for thiazolidinediones insulin-sensitizing agents used for treating type 2 diabetes mellitus.,
| Conclusion|| |
From the past few decades, miRs have evolved as a one of the dominant epigenetic regulators of gene expression during both normal, as well as diseased condition. However, their role in diseased phenotype of DbCM is still at a very nascent stage. Strategies like single miRs regulating the expression of multiple target genes and vice versa need to be exploited in DbCM therapeutics.
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Conflicts of interest
There are no conflicts of interest.
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