Role of microRNA in diabetic cardiomyopathy: From mechanism to intervention

    Role of MicroRNA in Diabetic Cardiomyopathy: from Mechanism to Intervention Rui Guo, Sreejayan Nair PII: DOI: Reference:

S0925-4439(17)30100-X doi:10.1016/j.bbadis.2017.03.013 BBADIS 64719

To appear in:

BBA - Molecular Basis of Disease

Received date: Revised date: Accepted date:

14 September 2016 6 February 2017 21 March 2017

Please cite this article as: Rui Guo, Sreejayan Nair, Role of MicroRNA in Diabetic Cardiomyopathy: from Mechanism to Intervention, BBA - Molecular Basis of Disease (2017), doi:10.1016/j.bbadis.2017.03.013

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ACCEPTED MANUSCRIPT Role of MicroRNA in Diabetic Cardiomyopathy: from Mechanism to Intervention

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Rui Guo and Sreejayan Nair*

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University of Wyoming, School of Pharmacy, College of Health Science and Center for

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Cardiovascular Research and Alternative Medicine, Laramie, WY 82071, USA.

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Running title: microRNA and diabetic cardiomyopathy

Correspondence: *

Sreejayan Nair, University of Wyoming, School of Pharmacy, Laramie, WY 82072, USA, Ph: 307-766-6138, Email: [email protected]

ACCEPTED MANUSCRIPT Abstract

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Diabetic cardiomyopathy is a chronic and irreversible heart complication in diabetic patients, and is characterized by complex pathophysiologic events including early diastolic dysfunction,

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cardiac hypertrophy, ventricular dilation and systolic dysfunction, eventually resulting in heart

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failure. Despite these characteristics, the underlying mechanisms leading to diabetic

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cardiomyopathy are still elusive. Recent studies have implicated microRNA, a small and highly conserved non-coding RNA molecule, in the etiology of diabetes and its complications,

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suggesting a potentially novel approach for the diagnosis and treatment of diabetic cardiomyopathy. This brief review aims at capturing recent studies related to the role of

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microRNA in diabetic cardiomyopathy.

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Keywords: diabetic cardiomyopathy, heart failure, microRNA, mechanism, biomarker, therapeutic intervention.

ACCEPTED MANUSCRIPT Introduction

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Diabetes mellitus, a common chronic disease worldwide, is a major risk factor for cardiovascular disease. It is estimated that there will be 300 million diabetic patients

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representing a prevalence of 5.4% across the world by 2025 [1]. Cardiovascular disease is the

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leading cause of death among people with diabetes, and ~70% of this mortality has been

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attributed to coronary artery disease. Interestingly however, a fraction of diabetic subjects exhibit heart failure even with normal coronary artery status and blood pressure, which is

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clinically characterized as diabetic cardiomyopathy [2]. From previous reports, the prevalence of diabetic cardiomyopathy approximates 50% among subjects diagnosed with clinical or

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preclinical stages of diabetes [3, 4], and accounts for ~ 22% of elderly people over age 65 [5]. Diabetic cardiomyopathy is characterized by cardiac hypertrophy, ventricular dilation,

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contractile dysfunction, which eventually results in maladaption and heart failure. The pathogenesis of diabetic cardiomyopathy still remains controversial, although several molecular and cellular mechanisms have been postulated. These mechanisms include, but not limited to excessive oxidative stress, fibrosis, apoptosis, and inflammation caused by hyperglycemia. Recent evidence indicates that microRNAs (miRNA) play important role in the pathogenesis of diabetic cardiomyopathy. Despite the numerous clinical studies on cardiovascular disease in diabetic subjects, successful pharmacological intervention for diabetic cardiomyopathy is still evasive, warranting newer strategies to treat this condition. In this review, we discuss the role of miRNAs in regulation of the pathophysiological events leading to the development of diabetic

ACCEPTED MANUSCRIPT cardiomyopathy and their emerging clinical roles as predictive and diagnostic biomarkers, as

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well as potential therapeutic targets.

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Overview of cardiomyopathy

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According to National Institutes of Health (NIH) and American Heart Association (AHA), cardiomyopathy is a collective term that refers to a disease of heart muscle (myocardium) that is

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abnormally enlarged, thickened and/or rigid. In most cases, the development of cardiomyopathy

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is chronic and progressive. The structural and functional abnormalities of the myocardium invariably cause cardiac dysfunctions, and can lead to arrhythmias, heart valve problems, heart

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failure, peripheral edema or other complications [6-9]. Cardiomyopathy can be inherited

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because of gene mutation/defects, or be acquired due to coronary heart disease, obesity, diabetes,

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chronic alcoholism, endocrine diseases, amyloidosis, sarcoidosis, hypertension, infection, autoimmune disease and drug toxicity. Generally, cardiomyopathy can be categorized as dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy and arrhythmogenic right ventricular dysplasia.

Dilated cardiomyopathy is the most prevalent from of cardiomyopathy, and is characterized by the enlargement of ventricular chambers and systolic dysfunction in the absence of coronary artery disease, hypertension or valvular disease [10]. The incidence of dilated cardiomyopathy is estimated at 1 in 2,500 individuals in the United States, and its occurrence is about twice as common as hypertrophic cardiomyopathy. Dilated cardiomyopathy is associated with a high mortality rate with ~50% of patients diagnosed with dilated cardiomyopathy dying within five years of diagnosis. Dilated cardiomyopathy is also the most

ACCEPTED MANUSCRIPT common reason for the heart transplantation [11-13]. In addition to idiopathic and familial dilated cardiomyopathy, coronary heart disease (ischemia), valvular heart disease, nutrition

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insufficiency, infection, myocarditis, hypertension, alcohol toxicity, diabetes, certain drugs and

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toxins, complications of pregnancy during the last months can also contribute to the

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development of dilated cardiomyopathy. Under stress conditions, such as chronic alcohol consumption and hypertension, the heart initially becomes hypertrophic, which is manifested as

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thickened ventricular walls and alterations in cardiac architecture as a result of cardiac

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remodeling, as well as the resistance against the cardiomyocyte contraction and stretching, which eventually leads to dilated ventricular walls (dilated cardiomyopathy).

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Diabetic cardiomyopathy and heart failure

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Diabetic cardiomyopathy often exhibits a long subclinical period in most patients, before diagnosis of the symptoms [14, 15], therefore referred to as a silent killer. In general, diabetic cardiomyopathy proceeds in three different stages: the asymptomatic (early) stage, diastolic stage and systolic dysfunction (late) stage [16]. The myopathic state of the diabetic heart often exhibits ventricular dilation, diastolic dysfunction, decreased or preserved systolic function, compensatory cardiomyocyte hypertrophy, and reduced ejection fraction and cardiac output, eventually resulting in maladaption and heart failure [17-19]. Diabetes is an independent risk factor for heart failure and diabetic patients exhibit four times increased risk for heart failure compared to the general population [20]. In diabetes, the incidence of congestive heart failure (CHF) is ~2.5 fold higher and CHF develops on average of 5.5 years earlier than in age-and sex-matched non-diabetic subjects [21, 22]. Framingham Heart Study shows that the incidence

ACCEPTED MANUSCRIPT of heart failure increased in diabetic patients despite adjustment for obesity, dyslipidemia, hypertension, or coronary artery disease [23]. Furthermore, the prevalence of heart failure has

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been shown to be closely correlated with abnormal glucose regulation and elevated glycosylated

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hemoglobin (HbA1c) levels [24-26]. An important pathophysiological mechanisms in

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progression to heart failure in diabetes is the increased risk of hypertension, which leads to increased afterload and pressure overload, eventually volume overload [25]. Interestingly,

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dipeptidyl peptidase-4 (DPP4), a key enzyme that regulates glucose metabolism has been

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reported as a potential biomarker in the diagnosis of diastolic heart failure in the patients of diabetic cardiomyopathy, further substantiating the pivotal role of glucose dysregulation in

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diabetic cardiomyopathy [27].

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Molecular and cellular mechanisms of diabetic cardiomyopathy The pathologic progression of diabetic cardiomyopathy is multifactorial and complicated. Several mechanisms have been involved in the pathogenesis of diabetic cardiomyopathy. Among the molecular mechanisms that trigger the progression of diabetic cardiomyopathy include metabolic disturbances (hyperglycemia and hyperlipidemia), insulin resistance/hyperinsulinemia, coronary microvascular disease, stimulation of sympathetic nerve system (SNS) and renin-angiotensin-aldosterone system (RAAS), autoimmunity defects, increased cytokines, cardiac autonomic neuropathy and epigenetic changes [28-30]. In diabetes, insulin resistance leads to increase in the accumulation of free fatty acids (FFA) in the plasma, which augments the FFA oxidation and utilization, generating a suppression of glucose oxidation in the heart [31]. The disorder of cardiac substrate metabolism

ACCEPTED MANUSCRIPT was believed to be linked with hypertrophic and dilated cardiomyopathy by altering myocardial pro-growth pathways and insulin signaling [32, 33]. In addition, increased β-oxidation of fatty

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acid increases mitochondria burden, leading to mitochondrial oxidative stress and generation of

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excessive reactive oxygen species (ROS). ROS in turn can induce apoptosis, trigger

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endoplasmic reticulum (ER) stress and attenuate levels of cardiolipin and ATP [29, 30, 32, 34]. Activation of RAAS has also been implicated in oxidative damage, apoptosis, necrosis and

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cardiomyocyte hypertrophy and cardiomyopathy both in diabetic subjects and animal models of

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diabetes [35, 36]. Thus, oxidative stress has been implicated as the main molecular and cellular mechanism leading to cardiomyopathy. Additionally, cardiac fibrosis and inflammation caused

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by increase in angiotensin II and aldosterone, together with elevated proinflammatory cytokines,

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are thought to be the other important players in the pathophysiology of diabetic cardiomyopathy.

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Furthermore, autophagy, impaired angiogenesis, endothelial dysfunction, dysregulation of microcirculation, disturbance of calcium signal, altered gene expression and proteins dysfunction are also associated with diabetic cardiomyopathy and cardiac dysfunction [14, 37, 38]. Epigenetics, especially alterations of miRNA, are emerging as important players in the etiology of diabetic cardiomyopathy and heart failure, which forms the basis of this discussion. MicroRNA MicroRNAs belong to the members of natural, endogenous and single-stranded molecules consisting of approximately 22 non-coding nucleotides that are evolutionarily conserved [39]. As an important family of gene regulators [40], they are well equipped to modulate gene expression through suppression of messenger RNA (mRNA) expression, initiation of mRNA

ACCEPTED MANUSCRIPT degradation, deadenylation, and sequestration resulting in the inhibition of protein translation [41]. The biogenesis and maturation of miRNA, as a part of transcriptional and post-

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transcriptional regulation process, has been well described in previous publications [42-44].

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Basically, there are two pathways involved in the miRNA biogenesis in animals. First, in the

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canonical pathway, the genes (DNA) coding intergenic miRNA in the nucleus are transcribed by polymerase II into primary mRNA (pri-mRNA) that is further recognized and cleaved at the

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distal stem portion by a ribonuclease III (RNase III) endonuclease, Drosha, together with its

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essential cofactor DiGeorge syndrome critical region gene 8 (DGCR8) into a shorter hairpin called precursor miRNA (pre-miRNA). The stem-loop structural pre-miRNA containing about

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70 nucleotides is subsequently exported into the cytoplasm from nucleus by transport factors

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Exportin 5 and Ran-GTP, and cleaved by another RNase III endonuclease, Dicer, associated

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with a protein activator of the interferon induced protein kinase (PACT), double-stranded RNA binding protein and TAR RNA binding protein (TRBP) into a double-stranded miRNA, with only 20-22 nucleotides. Subsequently, the miRNA duplex is loaded into argonaute (AGO) proteins such as AGO2 for the formation of the RNA induced silencing complex (RISC). The guide miRNA maintained in the RISC is mature miRNA, and it recognizes the 3’ untranslated region (UTR) of the target mRNA for its inhibition, degradation, modification, or the suppression of translational machinery. Sometimes miRNA can also increase mRNA activation via direct and indirect mechanisms such as the repression of the inactive mRNA, chromosomal remodeling, microribonucleoprotein (microRNP) regulation, or binding to the specific sites of the target mRNA (e.g. AU-rich element or 5’UTR) [45-47]. Second, non-canonical miRNA biogenesis pathways, including those that are independent of Drosha, Dicer or other protein

ACCEPTED MANUSCRIPT factors, are also being explored, although they have yet to be fully exploited. In brief, mature miRNAs can be produced by very short introns of the gene, termed mirtrons to directly form

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pre-miRNAs, and then access the canonical biogenesis pathway [43]. In some instances

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miRNAs can also be secreted through vesicular-like structures such as exosomes and apoptotic

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bodies [44]. Additionally, the post-transcriptional regulation of miRNAs also include RNA

recognition [48].

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Role of miRNA in diabetic cardiomyopathy

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editing, modification and decay which can potentially affect miRNA processing and target

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MicroRNA, DNA methylation and histone modifications are the general mechanisms of

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epigenetics, a term that describes studying the heritable change in the genome, which affects

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gene expression independent of the changes in DNA genome sequence [49]. Cardiac miRNAs are the recently discovered key modulators of gene expression in the heart which have been shown to contribute to both transcriptional and post-transcriptional regulation in diabetic cardiomyopathy and heart failure [39, 50, 51]. Both alterations in the synthesis of miRNA and levels of specific miRNA have been shown to play critical roles in cardiac remodeling and the development of heart failure [16, 52, 53]. The miRNAs may target mitochondrial function, ROS production, Ca2+ perturbation, apoptosis, fibrosis, pyroptosis, neurohormone secretion and reactivation of a fetal gene program, all of which are regarded as important mechanisms for cardiac hypertrophy, remodeling and heart failure progression [41, 54-58]. In addition, miRNA can affect other epigenetic changes such as alterations in histone H2A mRNA levels, histone deacetylase (HDAC) and DNA methyltransferases (DNMT), resulting in modulate gene

ACCEPTED MANUSCRIPT modification and expression [59]. Under high-glucose condition, miRNA-mediated signals can be transferred to other cells or tissues [44]. The stable levels of circulating miRNAs appearing in

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the blood can also be altered under different phases of diabetic cardiomyopathy. Taken together,

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miRNA may play a potential diagnostic, prognostic and therapeutic role in preventing and/or the

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treating diabetic cardiomyopathy.

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As indicated previously both the extent of miRNA synthesis and the levels of specific miRNA contribute to cardiac function and remodeling. For instance, conditional, cardiac-

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specific DGCR8 deletion in mice results in ventricular dysfunction followed by progressive ventricular dilatation and fibrosis [52]. Cardiac-selective knockout of Dicer in the post-mitotic

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stage leads to a significant decrease in cardiac contractility, severe dilated cardiomyopathy and heart failure in late cardiac development, and rapid progression to death within four days after

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birth. Mice with Dicer knockout initially developed ventricular hypertrophy, which eventually resulted in a dilated, hypofunctional ventricle [53]. To date, researchers have identified a number of miRNAs and their targeted mRNAs that are altered in diabetic cardiomyopathy or those that promote diabetic heart failure. These miRNAs exhibit essential roles in regulating genes related to cardiomyocyte hypertrophy, oxidative stress, cardiac fibrosis, apoptosis, pyroptosis, altered neurohormone signaling and fetal gene program. Among the miRNAs miR-21 [60], miR-320 [61], miR-141 [62], miR-30d [58], miR-34a [63], miR-301a [64], miR-451 [65], miR-206, miR-223 [66, 67], miR-483-3p [68], miR-216a, miR-221 [69], miR-195 [70], miR-199a-3p, miR-700, miR-142-3p, miR-24, miR-499-3p, miR208a and miR-705 [71] have often been found to be upregulated, whereas miR-133a [72, 73],

ACCEPTED MANUSCRIPT miR-150 [74], miR-29 [75], miR-144 [76], miR-378 [77], miR-499 [50], miR-143, miR-30c,

been found to be downregulated in under diabetic conditions.

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miRNA modulation in cardiac hypertrophy and fibrosis

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miR-181a [78], miR-9 [79], miR-23b [80], miR-1, miR-373, miR-20a and miR-220b [71], have

Diabetes can induce cardiomyocyte hypertrophy and fibrosis which are typical compensatory

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responses for developing cardiomyopathy. Several miRNAs have been implicated in cardiac

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hypertrophic signaling, including anti-hypertrophy miRNAs (miR-1, miR-133a, miR-373, miR378, miR-23b, miR-181a and miR-30c) and pro-hypertrophy miRNAs (miR-208a, miR-195,

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miR-221 and miR-451). miR-150, miR-199a, miR-214, miR-29a, miR-125b and miR-212 also

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have been associated with hypertrophic growth [77]. In addition, fetal gene program can be

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reactivated by miRNA during the development of cardiomyopathy and heart failure [81]. It was demonstrated that in diabetic cardiomyopathy both miR-133a and miR-373 are involved in myocyte enhancer factor 2C (MEF2C) signaling which is a key transcription factor for myocardial hypertrophy and mediates cardiac fibrosis through activation of p300 gene [82, 83]. Downregulation of miR-133a in diabetic cardiomyopathy resulted in an upregulation of serum and glucocorticoid regulated kinase 1 (SGK1) and IGFR1 resulting in the activation of myocyte specific enhancer factor 2C (MEF2C) [83]. Downregulation of miR-373 in diabetes was shown to be regulated by the p38 MAP kinase pathway. Overexpression of miR-373 in glucose-treated neonatal rat cardiomyocytes significantly decreased the cell size as well as reduced MEF2C levels indicating that MEF2C is a target gene of miR-373. In addition, miR-133a can also regulate calcineurin-nuclear factor in activated T cells c4 (NFATc4) signaling and DNA

ACCEPTED MANUSCRIPT methyltransferases (DNMTs) 1, -3a, and 3b, all of which are altered in diabetic hearts and have been shown to be associated with hypertrophic response and cardiac remodeling [41, 72, 83].

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Besides miR-133a, miR-1 is another muscle-specific miRNA that impacts cardiomyocyte

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growth by negatively regulating calmodulin and NFAT signaling. Ryanodine receptor Ca2+

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release channel complex (RyR2) located in sarcoplasmic reticulum is a target proteins for miR1 in the diabetic heart, and exerts a vital role in Ca2+ transport and cardiomyocyte contractility

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[84]. Moreover, miR-1 targets the 3’UTRs of MEF2A, transcription factor GATA binding

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protein 4 (GATA4), and other key cardiac-specific transcriptional factors such as heart and neural crest derivatives expressed 2 (Hand2), all of which exhibit essential role in myocardial

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differentiation, development and function [85-87]. MiR-208a, one of a positive regulator of

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hypertrophy is a cardiac-specific miRNA, and a possible inhibitor of Pim-1 expression [87].

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Overexpression of miR-208a leads to repression of myostatin and GATA4, as well as upregulation of β-myosin heavy chain (MHC) that contributes to cardiac hypertrophy [41, 54]. Calcium-binding protein (CAB) 39 has been suggested as a direct target of miR-451 in rat cardiomyocytes. Cardiomyocyte-targeted miR-451 knockout alleviated diabetic linked cardiac hypertrophy and contractile function in mice [65]. In addition to miR-133a and miR-373, several other miRNAs have been suggested to play a critical role in cardiac fibrosis, including miR-21, miR-125b, miR-150, miR-199a, miR29b, miR-30a, miR-142-3p and miR-700. For instance, studies by Liu and coworkers demonstrate that miR-21 levels are significantly augmented in cardiac fibroblasts treated with high glucose, which led to increase in collagen synthesis and an elevation of phosphorylated p38

ACCEPTED MANUSCRIPT MAPK [88]. Additionally, inhibition of miR-21 reduced fibrosis via blocking the activation of p38 signaling pathway, demonstrating a crucial role of miR-21 in diabetic cardiomyopathy.

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miR-142-3p and miR-700 have been shown to regulate cardiac fibrosis by modulating TGF-beta

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3 and Col1A1 in the heart [83]. In the heart of Zucker diabetic fatty (ZDF) rat, dysregulation of

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anti-fibrotic miR-29b has been linked with significant cardiac structural impairment such as disorganization of cardiomyocytes and myofibril bundles [89]. On the other hand, endothelial

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injury mediated by miRNA such as miR-200b may cause a phenotypic change resulting in

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cardiac fibrosis [90]. Additionally, miRNAs are also implicated in neurohormone signaling in diabetic subject via direct or indirect interaction with 3’UTR of natriuretic peptide receptor 3

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(NPR3) (e.g. miR-100), atrial natriuretic peptide (e.g. miR-425 and miR-21), Ang II (e.g. miR-

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132/212), angiotensin II type I receptor (e.g. miR-155) and beta-adrenergic receptor (e.g. miR-

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199a-5p), which contributes to both cardiac hypertrophy and fibrosis leading to diabetic cardiomyopathy [41, 54].

miRNA modulation in oxidative stress and mitochondrial damage Mitochondrial impairment and ROS accumulation including reduced oxygen (O2) metabolites, superoxide anion (O2−), hydroxyl radicals (•OH) and hydrogen peroxide (H2O2), were considered as major molecular and cellular mechanisms in the etiology of cardiac dysfunction and cardiomyopathy in diabetic subjects. Mitochondria are the major source for ROS in the living cells. Elevated glucose levels can lead to mitochondrial ROS production, resulting in the damage of cellular components. Mitochondrial dysfunction has bene shown to have a vital impact on cardiac anomalies associated with the diabetes [91-93].

ACCEPTED MANUSCRIPT Dysregulation of certain miRNAs including miR-144, miR-1, miR-133, miR-499, miR195, miR-34a, miR-141, miR-200a, miR200c, miR-19b, miR27a, miR-125b, miR-155 miR-

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146a, miR-210, miR-373 and miR-221 have been associated with oxidative stress [76, 77].

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Previous studies have shown that miR-499, miR-1 and miR-133 are remarkably decreased in

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high glucose-treated cardiomyocytes, while treatment with the antioxidant N-acetylcysteine notably restored the reduced levels of these miRNAs, leading to observable cardiac protection

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against diabetes-caused injury, demonstrating that downregulation of these miRNAs in diabetic

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heart were oxidative stress-dependent [84]. Similarly, the downregulation of miR-373 in diabetic cardiomyopathy was thought to be caused by hyperglycemia-induced oxidative stress in

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the heart [71]. Streptozotocin (STZ) or high glucose treatment decreased level of miR-144 that

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regulates ROS and apoptosis in the cardiomyocytes of mice by directly targeting nuclear factor-

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erythroid 2-related factor 2 (Nrf2) which is a central mediator of cellular response to oxidative stress. Particularly, members of miR-200 family such as miR-141, miR-200a and miR-200c play a crucial role in oxidative-stress dependent endothelial dysfunction, as well as in cardiovascular complications of diabetes and obesity. Increased miR-141 expression in diabetic heart is able to inhibit Slc25a that is a mitochondrial phosphate carrier, leading to reduced mitochondrial ATP production [83]. The p38α mitogen-activated protein kinase (MAPK), an oxidative stress sensor, is considered as a potential mechanism in the regulation of miR-200a and miR-141. In addition, miR-210 can target various mitochondrial components to modulate mitochondrial metabolism, and regulate ROS generation and activity [94]. miR-223 has also been shown to cause the

ACCEPTED MANUSCRIPT upregulation of the glucose transporter Glut4, thereby contributing to glucose uptake in

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cardiomyocytes under diabetic conditions [67].

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miRNA and cell death

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Apoptosis, autophagy, necrosis and pyroptosis are four pathways resulting in cell death, which plays important role in the pathological progression of diabetic cardiomyopathy. Several

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miRNAs have been associated with apoptosis, including miR195, miR-320, miR-378, miR-34a,

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miR-30d, miR-24a, miR-483-3p, miR-29, miR-181a and miR-30c. For example, miR-320 can target several genes such as vascular endothelial growth factor (VEGF), fibroblast growth factor

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(FGF), insulin-like growth factor (IGF-1) and IGF-1 receptor, and promote apoptosis in

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myocardial microvascular endothelial cells from type-2 diabetic rats [61]. Overexpression of

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miR-483-3p in diabetic mice exacerbates apoptosis in cardiomyocytes by transcriptional inhibition of IGF-1. Upregulation of miR-195 has been shown to lead to cardiomyocyte apoptosis, while miR-195 inhibition prevented apoptosis in cardiac endothelial cells in response to non-esterified fatty acid (NEFA) such as palmitate [70]. Increased miR-1 in diabetic heart resulted in downregulation of heat shock protein (HSP) 60 and Pim-1, leading to enhanced caspase-9 activity and apoptosis [95]. Moreover, miR-181a and miR-30c were identified to target genes of p53 and p21 which are key regulators of cardiomyocyte hypertrophy but also apoptosis. Both p53 and p21 were found to be upregulated by miR-30c and miR-181a in diabetic cardiomyopathy [78]. Furthermore, enhanced miR-141 in the diabetic heart disturbs the mitochondrial energy production which eventually results in cell death [83]. Repression of miR-

ACCEPTED MANUSCRIPT 144 prevented myocardial apoptosis by mitigation of oxidative stress in STZ-challenged diabetic

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mice [76]. Recent studies have attributed pyroptosis, the pro-inflammatory programmed cell death,

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in the pathophysiology of heart failure [58, 79]. Li and colleagues observed that upregulation of

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miR-30d in diabetic cardiomyopathy promoted cardiomyocyte pyroptosis leading to enhanced

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pro-inflammatory cytokines IL-1β and IL-18, as well as caspase-1. Furthermore, miR-30d directly suppressed FOXO3a expression and its downstream protein, apoptosis repressor with

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caspase recruitment domain (ARC). In contrast, deletion of miR-30d attenuated the pyroptosis in diabetic cardiomyopathy [58]. The latest research from Jeyabal’s and coworkers suggest that

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miR-9 may be implicated in diabetes-associated pyroptosis in ventricular cardiomyocytes. They demonstrated that reduced miR-9 in diabetic hearts activated caspase-1 and upregulated

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expression of ELAV-like protein (ELAVL) 1 which plays a critical role in progressive inflammation and heart failure. Interestingly, treatment with miR-9 mimics alleviated high glucose-triggered ELAVL1 and repressed pyroptosis in cardiomyocytes [79]. A growing number of studies have investigated the role of miRNA in regulating autophagy and mitophagy in Type 1 and Type 2 diabetes associated cardiomyopathy. Those miRNAs include miR30a, miR-133a, miR-212 and miR-221 [77]. It was demonstrated that miR-221 suppress autophagy and promotes heart failure by regulating p27-CDK2-mTOR cascade [96]. MicroRNAs such as miR-103, miR-107, miR-2861 and miR-874 were found to regulate myocardial necrosis in ischemia/reperfusion or myocardial infarction model [97-99].

ACCEPTED MANUSCRIPT Taken together, different miRNAs may regulate different mechanisms and signaling pathways in promoting or protecting against diabetic cardiomyopathy. These mechanisms

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indeed are closely correlated and interlinked. Emerging evidence suggest that alteration of

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certain miRNAs may impact serials of signaling transductions leading to oxidative stress,

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apoptosis, SNS and RAAS activation, hypertrophic response, fibrosis, oxidative stress and apoptosis, all of which works synergistically in the process leading to cardiomyopathy in

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cardiomyopathy is summarized in Table 1.

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diabetic subjects. Role of major candidate miRNAs in the development of diabetic

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Clinical application

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The fact that miRNAs are involved in the pathogenesis of diabetic cardiomyopathy by

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modulating various biological pathways suggest that these molecules may be harnessed a novel therapeutic strategy in treating diabetic cardiomyopathy. Furthermore, circulating miRNAs present in the blood are extremely stable and can be potentially used as diagnostic and prognostic biomarkers for cardiovascular diseases [66]. As circulating miRNAs can be altered depending on the phase of the disease they could also be used as potential biomarkers for assessing the development and progression of diabetic cardiomyopathy, consequently allowing early intervention [16, 100, 101]. Indeed, a number of miRNAs in plasma or whole blood have been reported in diabetic individuals, including miR-15a, miR-20b, miR-21, miR-24, miR-29b, miR-126, miR-150, miR-191, miR-197, miR-223, miR-320, miR-486, miR-28-3p [102], miR-9, miR-29a, miR-30d, miR-34a, miR-124a, miR-146a, miR-375 [103, 104], miR-144 and miR-192 [104], of which miR-126 and -144 are strongly associated with diabetes [102-107]. In addition,

ACCEPTED MANUSCRIPT plasma miR-503 has been associated with endothelial dysfunction and ischemia in diabetic patients [108]. Upregulation of plasma miR-222, miR-26a and miR-378a-5p have been reported

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in muscular dystrophic patients with cardiomyopathy, and plasma miR-222 has been suggested

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as a promising biomarker for monitoring cardiac structural changes [109]. Plasma miR-454,

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miR-500, miR-142-3p/5p and miR-1246 have been identified in patients with diastolic dysfunction [110]. Levels of miR-34a and miR-30d in human plasma has gained interest given

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their potential role in diabetes [58, 63]. Although no explicit determination of specific miRNAs

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(either in the heart tissue or the plasma) has been associated with diabetic cardiomyopathy in patients, it is likely that the circulating miRNAs observed in diabetes mellitus, are also

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associated with high risk of cardiomyopathy, and may play pivotal role in the pathology of

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diabetic cardiomyopathy. These miRNAs that would be highly related to diabetic

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cardiomyopathy includes miR-9, miR-21, miR-29, miR-30d, miR-34a, miR144, miR150, miR320 and miR378, which are summarized in Table 1. These miRNAs can be as potential serum biomarkers in patients with diabetic cardiomyopathy. Therefore, it likely that future studies will help unravel differential expression of specific microRNAs, which may provide as a biomarkers for early detection of diabetic cardiomyopathy. Developing anti-miRNAs and miRNA mimics to treat cardiomyopathy is an active area of research. Inappropriately elevated miRNAs which are shown to be causative of the disease can be targeted for knockdown or sequestration by the administration of antisense oligonucleotides such as antagomiRs, sponges and erasers [43, 44]. On the other hand, pathological downregulation of miRNAs can be replenished via the introduction of precursor

ACCEPTED MANUSCRIPT shRNA or double-stranded oligonucleotides with their coding sequences, which trigger the maturation of the targeted miRNAs for their functional implementation. AntagomiR-mediated

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miRNA suppression has been remarkably successful in animal models of heart failure,

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suggesting that antagomiR could become a potential approach for future therapeutic intervention

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to prevent diabetic cardiomyopathy. For example, intravenously injections of antagomiR targeting miR-132 efficiently inhibited endogenous miR-132 expression in the heart, and protect

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the heart against cardiac fibrosis, ventricular dilation, hypertrophy and heart failure, leading to

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improved cardiac function [111]. In vivo infusion of antagomiR for miR-133 induced notable and persistent cardiac hypertrophy [112]. However, the unwanted off-target effect of antagomiR

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may cause untoward adverse effects. In addition, the delivery of miRNA mimics in vivo

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confronts a lot of challenges such as lack of stability in the blood and less specificity, for

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example, each miRNA can modulate multiple mRNAs targets and gene expression, and it is especially hard to deliver them to the cardiovascular system [113]. Therefore, the delivery vehicles and method need to be further improved to increase delivery efficiency and improve the specific binding, as well as protect them against degradation. Nevertheless, the feature of miRNA non-specificity elicits a great advantage that enables a possibility of treating diseases with multiple pathologic mechanisms such as diabetic cardiomyopathy. To date, miRNA therapies that only target miR-122 and miR-34 are undergoing clinical trials for the treatment of hepatitis C and cancer respectively [41, 114, 115]. miR-208/499 and miR-15/195 antagomiRs have entered preclinical development stage for treating chronic heart failure and infarction remodeling respectively [116]. Large-animal studies and phase I/II trials on humans are still

ACCEPTED MANUSCRIPT lacking for cardiovascular medicine and more specific for diabetic cardiomyopathy, and the

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efficacy and toxicity test need to be further determined.

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Conclusion

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With the growing epidemic of diabetes mellitus and the associated cardiac complications, the value of miRNA as a new therapeutic target for diabetic cardiomyopathy and heart failure has

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garnered enormous interest among the scientific community. The noticeable alterations in

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miRNA profile detected in myocardium and the circulation mirrors the underlying molecular pathology of diabetic cardiomyopathy and diabetes-associated heart failure, making them

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attractive biomarkers. Identification and characterizations of miRNAs and the pathways they

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regulate may pave way for development of novel agents to treat or control diabetic

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cardiomyopathy in the near future.

Acknowledgement: The authors acknowledge the support of graduate assistantship for RG through a grant from the National Institute of General Medical Sciences (2P20GM103432) from the National Institutes of Health.

ACCEPTED MANUSCRIPT Table 1: Role of major miRNA candidates in the pathologic progression of diabetic cardiomyopathy Species/Animal model Rat heart /STZ Mouse heart/ISO

Pro-apoptosis

Mouse heart/STZ

[87]

miR-1/206

↑

Hsp60

Pro-apoptosis

Rat heart/STZ

[95]

miR-9

↓

ELAVL1

Anti-pyroptosis

Yes

[79]

miR-21

↑

DUSP8

Human diabetic heart IHVC/High glucose Primary NRCFs/ High glucose

Yes

[88]

miR-29

↑ ↓

ZDF rat heart Mouse heart/Acute MI

Yes

[89] [75]

miR-30c/181a

↓

p53/ p21

Pro-apoptosis/pro-hypertrophy

miR-30d

↑

FOXO-3a

Pro-pyroptosis

miR-34a

↑

Bcl-2

Pro-apoptosis

miR-133a

↓ ↓

SGK1/IGFR1 CTGF/TGF-β1

Anti-hypertrophy Anti-fibrosis

Mouse heart/STZ Mouse heart/STZ

[72] [117]

miR-141

↑

Slc25a3

Mitochondrial dysfunction

Mouse heart/STZ

[62]

miR-144

↓

Nrf2

miR-150

↓

p300

miR-195

↑

Sirt1/ B cell leukaemia/ lymphoma 2

miR-200b

↓ ↑

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SC

Pro-fibrosis

MA

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Cardiac structural damage Pro-fibrosis

D

MCL-1 COL1A1/ COL1A2/ COL3A1/FBN1

VEGF/p300/ SMAD2/SMAD3/ ZEB1/ZEB2

Promising serum biomarker

PT

Pathophysiological mechanism Anti-hypertrophy/oxidative stress Anti-hypertrophy

↑

Regulated genes RyR2 MEF2A/GATA4 NRVMs/ET1, ISO Pim-1

Mouse heart/HFD plus STZ H9c2 cells/High glucose Rat heart/ HFD NRVMs/High glucose H9c2 cells/High glucose

References [84] [86]

[78] Yes

[58]

Yes

[63]

Anti-apoptosis/ anti-oxidative stress

Mouse heart/STZ Cardiomyocytes/high glucose

Yes

[76]

Anti-hypertrophy Oxidative stress

Mouse heart/STZ NRVMs/High glucose

Yes

[74]

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Expression ↓

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miRNA miR-1

Pro-apoptosis/pro-hypertrophy/ oxidative stress

Pro-fibrosis

Mouse heart/STZ Db/db mouse heart Cardiac ECs/Palmitate

[70]

Pro-inflammation

Mouse cardiac ECs/STZ ECs/High glucose Db/db mouse aortal VSMC

[90] [118]

Pro-inflammation Oxidative stress

Db/db mouse aortal VSMC Db/db mouse thoracic aortas/MAECs

[118] [119]

miR-200c

↑

ZEB1/ZEB2

miR-208a

↑

Pim-1 Myostatin/GATA4

miR-221

↑

p27

miR-223

↑

Glut4

miR-320

↑

VEGF-c/Flk-1/IGF-1 /IGF-1R/ FGFs

miR-373

↓

MEF2C

miR-378

↓ ↑

IGFR1

miR-451

↑

CAB 39

Pro-hypertrophy

Mouse heart/HFD

[65]

miR-483-3p

↑

IGF1

Pro-apoptosis

Mouse heart/STZ H9c2 cells/High glucose

[68]

Pro-apoptosis Pro-hypertrophy

Mouse heart/STZ Mouse heart/TAB

[87] [120]

Impaired autophagy

Mouse heart/TG miR-221 overexpression

[96]

Disturbance of glucose metabolism

Ventricular biopsies from type 2 diabetic patient/NRVMs

[67]

Pro-apoptosis

Anti-hypertrophy Anti-oxidative stress Anti-hypertrophy Pro-apoptosis

GK rat cardiomyocytes GK MMVEC Mouse heart/STZ NRVMs/high glucose Cardiomyocytes/PE or AngII Mouse heart/STZ

Yes

[61]

[71, 84] Yes

[121] [77, 122]

ACCEPTED MANUSCRIPT

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Abbreviations in Table 1: Ang II: angiotensin II; ECs: endothelial cells; GK: Goto-Kakizaki; HFD: high-fat diet; IHVC:

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Immortalized human ventricular cardiomyocytes; ISO: isoproterenol; MAECs: Primary mouse

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endothelial cells; MI: myocardial infarction; MMVEC: myocardial microvascular endothelial

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cells; NRCFs: neonatal rat cardiac fibroblasts; NRVMs: neonatal rat ventricular cardiomyocytes;

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transgenic; ZDF: Zucker diabetic fatty

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PE: phenylephrine; Rap: rapamycin; STZ: streptozotocin; TAC: thoracic aortic banding; TG:

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ACCEPTED MANUSCRIPT Highlights:

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Diabetic cardiomyopathy is a chronic and irreversible heart complication. Emerging role of microRNA in the etiology of diabetes and its complications, suggest the potential of harnessing

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microRNA for the diagnosis and treatment of diabetic cardiomyopathy.