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Epigenetics in diabetic cardiomyopathy

Clinical Epigenetics volume 16, Article number: 52 (2024) Cite this article

Abstract

Diabetic cardiomyopathy (DCM) is a critical complication that poses a significant threat to the health of patients with diabetes. The intricate pathological mechanisms of DCM cause diastolic dysfunction, followed by impaired systolic function in the late stages. Accumulating researches have revealed the association between DCM and various epigenetic regulatory mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and other epigenetic molecules. Recently, a profound understanding of epigenetics in the pathophysiology of DCM has been broadened owing to advanced high-throughput technologies, which assist in developing potential therapeutic strategies. In this review, we briefly introduce the epigenetics regulation and update the relevant progress in DCM. We propose the role of epigenetic factors and non-coding RNAs (ncRNAs) as potential biomarkers and drugs in DCM diagnosis and treatment, providing a new perspective and understanding of epigenomics in DCM.

Introduction

According to the International Diabetes Federation, the population with diabetes is estimated to reach 600 million by 2045 [1], posing a critical threat to the health and safety of individuals and causing a heavy burden on medical care worldwide. Patients with diabetes primarily develop cardiovascular complications, which are the primary contributors to mortality. Diabetic cardiomyopathy (DCM), defined by Rubler et al. in 1972 [2], is a clinical condition caused by abnormal glycolipid metabolism that develops into heart failure without coronary heart disease, hypertension, or valvular disease [3]. As a typical metabolic cardiomyopathy, it includes the early subclinical period, which manifests as diastolic dysfunction, characterized by cardiac hypertrophy and myocardial fibrosis, and evolves to systolic dysfunction accompanied by heart failure with reduced ejection fraction [4]. Emerging studies have shown that patients with diabetes have a three to five times greater risk of adverse cardiovascular events than those without the disease [5]. Unfortunately, there are no specific drugs targeting the pathological mechanism of DCM.

Continuous impairment and cascade reactions induced by hyperglycemia and insulin resistance cause irreversible cardiac damage owing to a combination of genetic and environmental factors [6]. Researchers have attempted to elucidate the underlying mechanisms of DCM, which are usually treated as determinants of uncontrollable persistent pathological changes, such as aberrant hyperglycemia, insulin resistance, excessive oxidative stress, inflammatory response, and mitochondrial dysfunction [7,8,9]. However, the pathological mechanisms involved in the pathophysiology of DCM have not yet been fully elucidated.

Epigenetics is a heritable and invertible pattern without alterations in the DNA sequence and is closely related to environmental stimulations [10]. When first proposed by Waddington in 1942 [11], it had attracted researchers and has been applied to elucidate the underlying pathophysiological processes. Epigenetics has expanded the understanding of the fundamental pathological changes in biological development. Several studies have confirmed that epigenetic regulation is involved in the development of various diseases, particularly cardiovascular diseases. Given the genetic and environmental factors involved in the progression of DCM, we believe that fully elucidating the mechanisms underlying the pathogenesis of DCM based on epigenetic regulation will provide strong support for exploring effective therapeutic drugs. Recently, an increasing number of epigenetic regulatory mechanisms have been investigated with the development of sequencing technology. In this review, we focus on the advanced epigenetic progress in DCM to provide scientific and theoretical support for identifying novel potential intervention targets for clinical translation.

Overview of epigenetics

Epigenetic regulation serves as a bridge between the environment and heritable disease phenotypes. The fundamental modes of epigenetic regulation can be classified into three types: DNA methylation, histone modification, and non-coding RNA (Fig. 1).

Fig. 1
figure 1

Diagrammatic representation of three main epigenetic models. The gene expression could be modulated at multiple levels, including histone modifications, DNA methylation, and non-coding RNAs. Briefly, the histone post-translational modifications are categorized as two types. Repressive histone modifications including H3K27me3 and H3K9me3 mainly distributed in the heterochromatin region, where the chromatin structure is tight. Active histone modifications are divided into H3K4me1, H3K4me3, and H3K27ac. They are mainly distributed in the autochromatin region, which is more conducive to the gene transcription. DNA methylation on CpG islands plays different roles in gene expression depending on the number of methyl as well as the modification sites. Various non-coding RNAs generated by transcription of non-coding regions also regulate gene expression in the nucleus or cytoplasm at transcriptional or post-transcriptional levels

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DNA methylation

DNA methylation was the earliest well-studied pattern of epigenetic modification in the 1960s [12], typically occurring on the fifth carbon atom of cytosine (5mC). DNA modification is associated with many cellular biological processes, such as transcriptional regulation, genomic imprinting, and X-chromosome inactivation.

The effects of DNA methylation on gene activity primarily depend on different genomic regions, including CpG islands, intergenic regions, and genomic regions. Genome-wide analysis has shown that CpG islands are present in 60% of the promoter regions of the human genome [13], suggesting that dynamic changes in DNA methylation influence gene transcription and may play a role in growth and development. Hypermethylation at the CpG island recruits repressive methyl-modulating factors and contributes to maintaining heterochromatin status. Therefore, DNA methylation inhibits gene expression. Similarly, in the intergenic regions, the expression of non-coding gene elements is negatively correlated with DNA methylation [14]. However, a few studies have shown that a high level of DNA methylation in the gene is associated with increased gene expression [15].

The status of total DNA methylation is regulated by three regulators: reader, writer, and eraser, which identifies, catalyzes, and removes, respectively. Transcription factors with sequence-dependent mCpG-binding activity bind to specific sequences, initiating the methylation process [16]. The production and maintenance of DNA methylation highly depend on three DNA methyltransferases (DNMTs) with different functions: Dnmt1, Dnmt3a, and Dnmt3b. Dnmt3a and Dnmt3b catalyze the unmodified DNA chain and mediate de novo methylation, whereas Dnmt1 participates in DNA replication and repair by methylating hemimethylated DNA [17, 18]. Removal of DNA methylation is mediated by the ten-eleven translocation (TET) enzyme families, including tet1, tet2, and tet3. The Dnmt and Tet families are closely associated with multiple cardiovascular diseases under various pathological conditions and environmental stress [19]. Dnmt3a/3b protein levels in the myocardium are reduced during the development from fetal to adult stages but are reactivated in transverse aortic constriction-induced cardiac hypertrophy due to increased CpG methylation in the myh6 promoter region [20]. CRISPR-Cas9-mediated Dnmt3a knockout in mice was found to aggravate severe cardiac dysfunction and fibrosis, and Dnmt1 participated in anti-apoptotic signaling pathways by regulating cardiac-specific gene methylation in the promoter [21]. Erasers such as tets promote cardiomyocyte differentiation at the cardiac progenitor stage during mouse and human cardiac development by deactivating the Wnt signaling pathway [22, 23].

Histone modifications

A vast amount of genetic information can be preserved and precisely regulated by the folded and supercoiled chromatin structures in cells. Nucleosomes contain five types of conserved histones (H1, H2A, H2B, H3, and H4) and spiral DNA of approximately 146 bp, which is the basic structure of eukaryotic chromatin. Various post-translational modifications, such as acetylation, methylation, phosphorylation, ubiquitination, phase polymerization, and ADP ribosylation, occur at the tail or acid pocket of histones, particularly of H3 and H4, which regulate gene expression by altering chromatin accessibility.

The modulating patterns of histone modifications are classified as activating and inhibitory histone modifications according to the regulatory effects of the process on gene expression. Lysine acetylation is usually associated with gene activation, particularly at histone H3 lysine 27. Histone H3 lysine 27 acetylation (H3K27ac) significantly loosens the folded and supercoiled structure of chromatin, which is beneficial for recruiting various transcription factors and coactivators to gene promoters, enhancing gene transcription [24, 25]. Owing to its significant effect on enhancing gene transcription, H3K27ac is considered a molecular marker of super-enhancers. Trimethylated histone H3 at lysine 27 (H3K27me3) is a typical repressive histone modification that compresses the chromatin to suppress gene transcription. The dynamic balance between the two types of histone modifications in chromatin determines disease progression. Professor C. David Allis proposed the histone code hypothesis, which states that the crosstalk between different histone modifications amplifies gene-modulating signals, leading to a greater effect on the chromatin structure of target genes. This has gained increasing attention from researchers.

Notably, multiple crucial molecules combine to maintain a balance in the regulatory network of histone modifications. For lysine acetylation, histone acetyltransferases (HATs) and histone deacetylases (HDACs) catalyze the acetylation and deacetylation of phosphorylated RNA Pol II, respectively [26]. Various studies have indicated those both are critical in cardiac pathological processes, such as myocardial hypertrophy, cardiac fibrosis, endothelial hyperplasia, and smooth muscle cell migration [27,28,29,30,31,32]. Bromodomain protein 4 (BRD4) is a well-known member of the bromodomain and extra-terminal domain (BET) family. As a vital transcriptional activator and regulator, BRD4 specifically recognizes histone acetylation sites via its bromine domain, recruits many transcription complexes, and promotes acetylation [32].

Given the central role of BRD4 in gene activation in tumors and heart failure, researchers have attempted to develop its inhibitors and targets, such as JQ1, which has been widely used in basic research and clinical trials. Similarly, for lysine methylation, there are numerous types of histone methyltransferases and demethylases (KDM family, comprising the LSD family with flavin adenine dinucleotide-dependent monoamine oxidases (MAO) and another family with Fe- (II) and α-ketoglutarate-dependent dioxygenases), to maintain chromatin homeostasis. Disruptor of telomeric silencing 1-like has been reported to regulate H3K79me2 of core transcription factors-nuclear factor kappa-B (Nf-κB), mediating inflammation in atherosclerosis development [33]. The widely studied methyltransferase, enhancer of zeste homolog 2 (EZH2, the subunit of multi-comb inhibitory complex 2 [PRC2]), whose inhibitors have been used in tumor therapy, participates in gene expression silencing by catalyzing H3K27me3 [34]. In addition, the switch from EZH2 to EZH1 reportedly mediates cardiac regeneration [35].

Non-coding RNAs

Even with the rapid development of high-throughput technology, scientists were surprised to discover that less than 2% of transcripts have protein-encoding potential in the human genome [36]. Several non-coding RNAs (ncRNAs) are considered to be gene-expressive noise and participate in regulating gene expression.

ncRNAs are usually classified into long non-coding RNA (lncRNAs) and small non-coding RNAs according to their sequence length. lncRNAs are long ncRNAs with lengths of > 200 nt, some of which can encode short peptides. They are less conserved across species and are highly cell-type-specific. Their functions are complex and are associated with their location. Diverse modulation models have been reviewed by Mendell et al. [37]. Nuclear lncRNAs are involved in many processes, such as chromatin dynamics and RNA splicing, by recruiting transcription factors or binding to transcriptional regulatory complexes, whereas cytoplasmic lncRNAs act as scaffolds for chromatin remodeling complex combinations or microRNA (miRNA) sponges to participate in mRNA transport and protein stability. Small non-coding RNAs can be further classified as miRNAs, circularRNAs, tRNA-derived small RNAs, and PIWI-interacting RNAs. Unlike lncRNAs, small non-coding RNAs are relatively conserved. miRNAs recruit miRNA-induced silencing complexes (MiRISCs) and bind to the 3' untranslated region (UTR) of their target genes, inhibiting gene translation. Similarly, nuclear miRNAs modulate target genes at the transcriptional level by binding to the promoters of the target gene.

Epigenetic regulation modes do not exist independently; they rather have interrelated influences, forming a complex regulatory network that collectively maintains the epigenetic regulatory homeostasis of genes. For example, a typical lncRNA-Hotair has been investigated to be related to multiple cardiovascular diseases. A previous study showed that Hotair could recruit the histone modification writer PRC2, affecting cell proliferation, differentiation, and metabolism by changing chromatin structure [38]. In addition, Hotair could bind to miRNA 331-3p as a competitive endogenous RNA and participate in tumor metastasis [39]. The scope of miRNA regulation is broad, given that small molecules and more than 30% of genes in the human genome are targeted and regulated by miRNAs. Multiple studies have shown that miRNAs target genes that encode histone-modifying enzymes, such as HDAC, DNMT, and EZH, thus highlighting the relationship among ncRNAs, DNA methylation, and histone modification [40, 41].

Epigenetic regulation in DCM

As a metabolic disease, DCM is susceptible to environmental factors, such as glycolipid homeostasis which vastly influences epigenetic states. Therefore, it is likely that epigenetic regulation plays a critical role in DCM. Based on the current researches, we describe the role of epigenetic regulations in DCM and provide new insights into the pathogenesis and treatment of DCM.

DNA methylation in DCM

DNA methylation is highly related to diabetic status and is crucial in vital pathological processes in DCM [42]. Various signaling pathways are activated under different levels of methylation, which occurs in the promoter regions of multiple metabolic genes.

JunD is a member of the AP-1 transcription factor family that is involved in cardiac aging, angiogenesis, and metabolic processes [43, 44]. Hussain et al. found that JunD expression was reduced in the heart tissues of patients with diabetes and DCM mice [45]. Cardiac-specific JunD overexpression ameliorated cardiac dysfunction by mitigating oxidative stress, inflammatory responses, and cardiac impairment in DCM. Various epigenetic modifications regulate JunD expression. Quantitative polymerase chain reaction was used to confirm that methylation of the JunD promoter region was up-regulated in diabetic hearts. Furthermore, DNA methylation-induced repressive epigenetic modifications, such as H3K9me3 and multiple endocrine neoplasia 1, were up-regulated. These results indicated that hyperglycemia-induced hypermethylation of the JunD promoter compressed the chromatin structure and inhibited JunD transcription.

Calcium imbalance is a pathological mechanism of DCM. As a transmembrane transporter, sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) is primarily distributed in cardiomyocytes and assists in transferring Ca2+ ions from the cytoplasm to sarcoplasmic reticulum, thereby maintaining calcium homeostasis in cardiomyocytes. Studies have shown that it significantly affects the development of various diabetic complications, particularly DCM [46, 47]. An early study showed that the methylation level of the SERCA2a promoter region was enhanced under tumor necrosis factor-alpha stimulation, and reduction of SERCA2a exacerbated calcium imbalance and oxidative stress in cardiomyocytes.

Glutathione peroxidase 1 (GPX1) is an antioxidant enzyme involved in DCM development; it reduces the production of reactive oxygen species (ROS) in cardiomyocytes and improves insulin resistance [48]. Given that DNMTs are associated with glycolipid and energy metabolism, several researchers have investigated their roles in DCM [49,50,51]. Many advanced glycation end products are produced in diabetic environments, which promote the methylation of the GPX1 promoter region, thereby aggravating oxidative stress and apoptosis in cardiomyocytes. Zhu et al. identified the exact enzyme that mediates the methylation process and found that DNMT2 is crucial in GPX1 expression [50]. Dnmt1, Dnmt3a, and Dnmt3b expression levels are downregulated in Akita diabetes. The suppressor of cytokine signaling (SOCS)1/3 promoter methylation is increased, and SOCS1/3 activates the JAK-STAT signaling pathway in hepatocytes and stimulates the transcription of insulin-like growth factor 1, which mediates oxidative stress in diabetic cardiomyocytes [52]. In addition, the renin–angiotensin–aldosterone system is overactivated during the development of DCM, inducing ventricular hypertrophy and remodeling. Studies have shown that the gene expression of angiotensin receptor 1b highly depends on the methylation level of its promoter [53]. Hypoxia-inducible factor methylation is associated with glucose metabolism and insulin sensitivity, which are the primary factors involved in DCM development. In a recent case–control study, HIF-3A levels decreased in the peripheral blood of patients with DCM [54]. Moreover, HIF3a mRNA expression and the intron 1 methylation rate were negatively correlated.

Histone modifications in DCM

Histone acetylation is involved in the pathogenesis of coronary artery disease, hypertension, arrhythmia, and heart failure and is the most studied form of histone modification in DCM [55].

Nicotinamide adenine dinucleotide (NAD +) -dependent sirtuin is a highly conserved class III deacetylase that targets the covalent modification of lysine at specific histone sites, exerts its epigenetic regulatory role, and acts as a transcription factor to modulate gene expression, thereby participating in various pathological processes of DCM, such as oxidative stress, inflammation, cell differentiation, mitochondrial metabolism [56,57,58]. Palomer et al. [59] reviewed the multiple functions of SIRT in DCM pathophysiology. A recent study indicated SIRT3 could mediate mitochondrial translation and protest against diabetes-induced cardiac dysfunction by reducing Ago2 malonylation from a new perspective [60]. Chen et al. found that HDAC inhibition attenuated cardiac hypertrophy and interstitial fibrosis in a streptozotocin (STZ)-induced diabetic model by increasing acetylated GLUT1 and phosphorylated p38 expression [61]. Additionally, HDAC inhibition reportedly had a cardioprotective effect within a short period of hyperglycemia treatment. Furthermore, Xu et al. found that HDAC3 appeared to be the most effective subtype [62]. In this study, the cardiac function of DCM mice treated with the specific HDAC3 inhibitor, RGFP966, was better than that of those treated with the pan-HDAC inhibitor, valproic acid. Previous studies indicated that diabetes results in impaired proliferation and reprogramming of cardiac-specific mesenchymal cells. Global histone code profiling of cardiac mesenchymal stem cells from patients with diabetes was performed to analyze epigenetic alterations, and the results indicated that H3K9Ac and H3K14Ac levels were decreased, while H3K9me3 and H3K27me3 levels were increased. Similarly, levels of some cardiac epigenetic enzymes, such as histone demethylase jmjd3, acetylase GCN5, and HAT activator SPV106, were significantly altered under diabetic conditions. These results indicated that epigenetic modifications of histones and chromatin remodeling are involved in diabetes-associated cardiac mesenchymal cell reprogramming [63, 64]. Endothelial progenitor cell-derived extracellular vesicles initiate cardiac repair mechanisms after myocardial infarction. However, Huang et al. found that reparative function was impaired in patients with diabetes and mice, suggesting that hyperglycemia aggravates cardiac dysfunction induced by ischemia–reperfusion injury [65]. Further exploration showed that endothelial gene transcription was inhibited by HDAC under diabetic conditions.

In addition to epigenetic modifier enzymes, some transcriptional regulators are reportedly involved in the progress of DCM (Fig. 2). Studies have shown that BRD4 is closely associated with metabolic diseases [66]. BRD4 binds to the promoters of multiple metabolic genes and regulates cardiac fibrosis and oxidative phosphorylation [67]. The activated NF-κB signaling pathway is an essential inflammation reflection pathway in DCM. BRD4 acts as a transcriptional coactivator of p65 to mediate NF-κB-induced gene transcription in β-cells [68].

Fig. 2
figure 2

Dynamics of non-coding RNAs interacting with histone modification in diabetic cardiomyopathy. Complex epigenetic crosstalk contributes to the progress of diabetic cardiomyopathy under the condition of hyperglycemia and hyperlipidemia. lncRNA DACH1 binds to deacetylase SIRT3, accelerating its ubiquitination-dependent degradation. However, lncRNA Hotair interacts with FUS and stabilize SIRT3 indirectly. The transcription of another deacetylase, SIRT1 is regulated by various miRNAs. miR-22, miR34a, and miR195 could bind to the 3’UTR region of sirt1 mRNA. In addition, MALAT recruits EZH which hold the methyltransferase activity, inhibiting miR-22 transcription by reducing H3K27me3. BRD4 as a coactivator of p65 identifies and activates inflammatory genes, playing a crucial role in inflammation and oxidative stress. With the combination of genetic and epigenetic factors, characteristic pathological changes such as hypertrophy, fibrosis, and apoptosis occur in the heart, resulting in diabetic cardiomyopathy ultimately

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Histone lactation is a novel epigenetic reprogramming pattern discovered and proposed by Zhao et al. in 2019 [69]. Lactic acid was found to act as a precursor to lactylate histones and not just as an energy substrate. Accumulating evidence indicates that histone lysine lactylation mediates various pathological progressions in cardiac disease, such as early repair of post-myocardial infarction and mitochondrial pyruvate carrier [70,71,72]. A recent study showed that α-myosin heavy chain (α-MHC) K1897 lactylation was significantly reduced in AngII-induced heart failure mice owing to decreased lactation [73]. The mutation on specific lactylate sites led to a weaker α-MHC–titin interaction and induced cardiac dysfunction. Furthermore, the formation and decomposition of histone lactylation are mediated by acyltransferase p300 and delactylase SIRT1, respectively. A recent study also demonstrated that deacetylase HDAC1-3 is involved in eliminating histone lactylation [74]. These results suggest a potential association between lactylation and cardiac metabolism and a crosstalk between different histone modifications. Studies on the role of histone lactation in the progression of DCM remain limited; however, it is worth anticipating that a potential epimetabolic code based on glycolytic products is a promising prospect.

ncRNAs in DCM

lncRNAs in DCM

The inflammatory response is considered an exacerbating factor in DCM development, which contributes to oxidative stress and apoptosis (Table 1) [75]. Nucleotide-binding and oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) is a cytosolic immune factor that assembles signaling complexes under various pathological conditions, such as metabolic abnormalities, mitochondrial dysfunction, aging, and environmental factors, mediating the activation of inflammatory reactions and cell death [76, 77]. NLRP3 can be activated upon hyperglycemia and hyperlipidemia stimulation and promotes the generation of pro-inflammatory factors, such as interleukin (IL)-1β, IL-6, and IL-18. Activated inflammatory factors induce apoptosis and pyroptosis, which aggravate the progression of DCM. Meng et al. found that lncRNA TINCR was significantly up-regulated in an STZ-induced DCM rat model, promoted cardiomyocyte pyroptosis, and aggravated cardiac dysfunction [78]. They further found that TINCR interacted with NLRP3 and stabilized NLRP3 mRNA, thereby accelerating the initiation and progression of DCM. lncRNA MALAT1-NLRP3 axis reportedly participated in various diabetic complications. In diabetic hearts, increased MALAT1 expression was found to aggravate cardiac pyroptosis and fibrosis. A previous study indicated that the protective effect of pomegranate peel extract on DCM relied on NLRP3/caspase-1/IL1β signaling pathway inhibition via the repression of MALAT1 expression. This suggested that MALAT1 could be a novel therapeutic target for DCM [79]. Another important lncRNA, GAS5, has been identified to be associated with metabolic disease by regulating NLRP3 [80]. The expression of GAS5 was reduced in high-fat diet-fed mice and involved in nonalcoholic fatty liver disease via NLRP3-mediated pyroptosis. In a study by Xu et al., lncRNA GAS5 expression decreased in STZ-induced DCM mouse hearts and high glucose-treated HL-1 cells. Moreover, downregulation of GAS5 promoted NLRP3 inflammasome activation and cardiac pyroptosis and exacerbated the development of DCM [81]. GAS5 acts as an miRNA-34b-3p sponge to enhance the expression of the aryl hydrocarbon receptor, negatively regulating the NLRP3 inflammasome.

Table 1 lncRNAs associated with diabetic cardiomyopathy
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Cardiac fibrosis is the characteristic feature in the advanced and late stages of DCM progression, in which the transforming growth factor beta (TGF-β)-SMAD signaling pathway is vital. Activated TGF-β triggers cellular profibrotic responses and further causes collagen deposition, cardiac remodeling, and stiffing. The lncRNA Kcnq1ot1 was activated in the cardiac tissue of an STZ-induced diabetic model compared with that in control C57BL/6 mice, suggesting that Kcnq1ot may be involved in the progression of DCM [82]. Functional in vivo and in vitro experiments using short hairpin RNA or small interfering RNA indicated that the systolic and diastolic functions of the diabetic heart were improved after silencing Kcnq1ot1, which manifested as reduced myocardial mass, inflammation, and fibrosis-related gene expression. Further, the TGF-β1/SMAD signaling pathway was markedly inhibited with Kcnq1ot1 knockdown and was rescued with repressed miR-214-3p, suggesting that lncRNA Kcnq1ot1 functioned as a miRNA sponge to regulate TGF-β1/SMAD pathway. Another lncRNA, AK081284, was proven to be associated with cardiac interstitial fibrosis via TGF-β1. Zhang et al. discovered that AK081284 mediated the effect of IL-17 on interstitial fibrosis in the diabetic heart [83]. Following AK081284 knockdown in cardiac fibroblasts, there was a reduction in mRNA expression of TGF-β and collagen synthesis genes. In addition, the lncRNA Crnde, which was primarily increased in CFs with TGF-β stimulation, was found to exert a protective effect against cardiac fibrosis. In addition, Crnde inhibited the transcriptional regulation of SMAD3 by binding to SMAD3 directly, forming a negative feedback loop between Crnde and SMAD3 [84].

Furthermore, some other lncRNAs are found to be associated with inflammation, apoptosis, and autophagy during the progression of DCM. The lncRNA HOTAIR ameliorates high glucose (HG)-induced pyroptosis and inflammation by recruiting the fused in sarcoma (FUS) protein and promoting SIRT3 expression [85]. In contrast, HOTAIR functions as a miRNA-34a sponge involved in oxidative stress [86]. Increased H19 expression under HG conditions inhibits apoptosis and inflammation by binding to different miRNAs [87, 88].

miRNAs in DCM

The widespread regulation of miRNAs during the development of DCM has gradually been revealed with advances in sequencing technology (Table 2). Different miRNA expression profiles have been reported at different stages of DCM [89].

Table 2 miRNAs related to diabetic cardiomyopathy
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MiRNAs regulate gene expression by binding to the 3’ UTR of different genes, implying that each may be involved in various pathologic processes of DCM. miRNA-30c expression levels were reduced in db/db mice, and its specific overexpression at the cardiac site ameliorated lipid accumulation, ROS generation, and apoptosis in cardiomyocytes. miRNA-30c can regulate myocardial metabolic disorder by binding to peroxisome proliferator-activated receptor-gamma coactivator-1 beta. In addition, miRNA-30c targets apoptosis-related genes, such as beclin1, p53, and p21, inhibiting diabetes-induced programmed cardiomyocyte death. The same downregulated miRNA133a in diabetic hearts is involved in cardiac remodeling. Combined with COL1A1, ERK1/2, and SMAD-2, miRNA133a suppresses collagen synthesis in the myocardial interstitium and cardiac fibrosis [90, 91]. Norepinephrine enhances the contractile capacity of the myocardium by activating beta receptors in cardiomyocytes. In DCM, β receptors are abnormally inactivated, and the contractile function of the heart is impaired. Nandi et al. [92] constructed miRNA-133a transgenic mice and unveiled that miRNA133a improved the contractile function of the diabetic heart by binding to the 3' UTR of tyrosine aminotransferase and promoted the synthesis of norepinephrine.

Several studies have confirmed the protective effects of miR-21 against cardiovascular diseases. miR-21 can improve fibrosis and apoptosis of cardiomyocytes; moreover, the hypoglycemic drug vildagliptin exerts hypoglycemic and cardioprotective effects through the miR-21/SPRY1/ERK/ mammalian target of rapamycin pathway [93]. The p38/ mitogen-activated protein kinase (MAPK) signaling pathway is significantly activated in diabetes and is involved in various pathological processes of DCM, such as oxidative stress, apoptosis, and ventricular remodeling [94]. HG-induced miR-21 overexpression activates the downstream p38/MAPK pathway and, thus, participates in ventricular remodeling in DCM [90].

Further, miR-320 is specifically expressed in the cardiomyocytes of DCM mice and can be detected in the plasma even before cardiac diastolic function is affected [95]. Knocking out miR-320 in DCM mice significantly improved glycolipid metabolism and cardiac function. This suggests that miR-320 is crucial in DCM and may be a potential target for its diagnosis and treatment. Unlike cytoplasmic miRNAs, nuclear miR-320 could bind to the promoter of the fatty acid receptor CD36 gene, leading to its expression.

Potential clinical application of epigenetic regulators in DCM

Epigenetic biomarkers

There are no obvious symptoms at the subclinical period of DCM, which makes detection and diagnosis more difficult. Serial studies have demonstrated epigenetic biomarkers play a vital impact on the early diagnosis and treatment of DCM over the last decade.

DNA methylation could be detected in blood and has been reported to be associated with the occurrence of cardiovascular diseases and diabetic complications. Hu et al. [96] identified that the hypomethylation of vascular endothelial growth factor (VEGFB), placental growth factor (PLGF), phospholipase C beta 1(PLCB1), and fatty acid transport protein 4 (FATP4) was associated with the incidence of diabetes with cardiovascular diseases, prompting that DNA methylation level might be a potential biomarker. Interestingly, in a new cross-sectional analysis, researchers found that increased DNA methylation age was related to cardiometabolic risk and worse cardiovascular prognosis, indicating the function of promising biomarkers [97]. In addition, Gadd et al. [98] utilized a machine learning strategy to construct a diabetes-associated epigenetic scores tool. The tool based on the genetic information carried by DNA methylation could depict methylation-proteomic features for diabetes prediction and risk stratification, including diabetic heart disease.

NcRNAs, especially miRNAs, have also emerged as potential lipid biopsy biomarkers in diabetic heart diseases owing to their availability and stability in biofluids. In a previous review by Jin, miRNAs targeting diabetes-associated cardiac fibrosis, which may act as potential biomarkers, had been summarized [99]. Here we mainly focused on the recently validated ncRNAs in human studies. Bielska A et al. indicated that five up-regulated miRNAs (miR-615-3p, miR-3147, miR-1224-5p, miR-5196-3p, and miR-6732-3p) in serum showed high diagnostic value (AUC > 0.8) for diabetic patients with ischemic heart disease [100]. Furthermore, in a 5-year prospective study, increasing cardiac hypertrophy of diabetic patients was paralleled by the up-regulation of miR122-5p, which was independent of glycemic control [101]. To further investigate the underlying mechanism, they constructed the diabetic mice model and found that miR122-5p was involved in diabetic cardiomyopathy by modulating extracellular matrix gene expression. These indicated the potential of miR-122 expression in evaluating the early stage of DCM, which was characteristic of subclinical diastolic dysfunction.

Potential epigenetic therapies in DCM

In recent years, drug development based on several epigenetic regulatory molecules has improved the treatment of various diseases. Small-molecule inhibitors, such as azacitidine and decitabine, which target DNMTs and alleviate the inhibition of gene transcription due to methylation, have been applied in the treatment of myelodysplastic syndrome. Although drugs targeting enzymes involved in DCM remain unexplored, some recent discoveries may inspire research in this area. A real-world study showed that DNA methylation is associated with hypoglycemic drug response. Sonia et al. evaluated genome-wide DNA methylation in patients with type 2 diabetes mellitus and found that patients whose genomes showed greater methylation were more likely to tolerate metformin. They used combined weighted methylation risk scores based on 11 methylation sites to analyze the potential of DNA methylation to identify the risk of metformin tolerance, with the area (AUC) under the ROC more than 0.8 in different cohorts [102]. These results suggest that DNA methylation could serve as a predictive factor for medication evaluation. HDAC inhibitors have been developed in the clinical treatment of cancer. However, studies in the cardiovascular field remain in the preclinical stage. Travers et al. [31] found that HDAC inhibitors improved cardiac diastolic dysfunction. In their study, they constructed a diastolic insufficiency model via unilateral nephrectomy and injection of deoxycorticosterone acetate and found that the HDAC inhibitor ITF2357 could significantly inhibit cardiomyocyte fibrosis and ameliorate ventricular remodeling. Notably, diastolic dysfunction is a typical feature in the early stages of DCM. Therefore, conducting an in-depth study of HDAC inhibitors for the treatment of DCM holds great promise.

Studies on the application of BRD4 inhibitors in DCM treatment showed initial results. However, these studies were primarily conducted with animal models. In DCM mice, JQ1 significantly improved mitochondrial function, inhibited cardiomyocyte apoptosis and fibrosis, and improved diabetes-induced cardiac impairment [103]. Another BRD4 inhibitor, apaberon (APA), significantly ameliorated diabetic peripheral vascular damage. A recent large randomized double-blind clinical trial showed that the addition of APA to standard medical therapy did not significantly improve the incidence of major cardiovascular events in patients with acute coronary syndrome, type 2 diabetes, and low levels of high-density lipoprotein [104]. A subgroup analysis on the association between APA and type 2 diabetes remains lacking.

Given the prominent gene-silencing function of small RNAs in disease progression, RNA-based therapeutics have become a vital research direction for drug development. miR-10b-5p miRNA-targeted drugs act on pancreatic and fat cells to improve insulin resistance [105]. However, their safety, efficacy, and effects on DCM should be confirmed through further clinical studies.

Epigenetic editing

The rapid advancement of epigenome editing technology from Zinc-finger, transcription activator-like effectors (TALEs) to the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (cas9) dCAS9 technique shows us a novel and breakthrough direction for the treatment of diseases [106, 107]. Though there was still no research focusing on DCM, the application of epigenetic editing in metabolic diseases did give us some inspiration. Ou et al. [108] investigated epigenome editing technology as a promising tool for inducing β cell proliferation previously. In their research, the methylation levels of the imprinting control region 2 (ICR2), which affected the expression of cell cycle inhibitor p57, were significantly reduced by TALE in pancreatic islets B cells. Recently, the dCAS9 system based on epigenetic regulatory factors precisely regulated disease-related genes while preserving the integrity of the genome. Matboli et al. [109] used CRISPR/CAS9 to knockout LncRNA-RP11-773H22.4 in peripheral blood mononuclear cells (PBMCs) of T2DM patients, and insulin resistance-related genes were altered significantly. Of note, the latest research published in Nature proposed a novel epigenome editing tool, EvoETR, with more powerful efficiency and specificity compared with CRISPR cas9 epi-silencing [60]. EvoETR-mediated PCSK9 inhibition in mice lasted for one year in mice, laying the foundation for effective in vivo therapeutics based on epigenetic editing.

Indeed, there are plenty of challenges to the application of epigenome editing in clinical practice, such as off-target and nonspecific effects. However, site-specific epigenetic modifications remain a very active area of translational research, warranting the need for more studies.

Conclusions and future perspectives

DCM is a unique manifestation of systemic metabolic disorders caused by hyperglycemia or hyperlipidemia in the heart and is the most severe diabetic complication. In this review, we focused on the epigenetic regulation in DCM. First, we reviewed the basic epigenetic regulation patterns, including DNA methylation, histone modification, and ncRNAs. Then, we went to current investigations into the mechanisms of epigenetic regulation, which form a complex network that regulates gene expression at the transcriptional and post-transcriptional levels in DCM. Due to the feature of availability and stability in biofluids, a great number of epigenetic modifiers could serve as potential biomarkers for the early diagnosis and treatment of DCM. Although limited and remaining in the animal experimental stage, all available evidence about drugs targeting epigenetic regulators in DCM show that epigenetic modifiers hold great promise for the treatment of DCM.

It is noteworthy that issues and challenges exist in the mechanism investigation and clinical translation. Epigenetic modifications and ncRNAs play vital roles in metabolic memory. However, researches on the function of epigenetic modifications and ncRNAs underlying hyperglycemic memory are limited. Although current studies indicate strong therapeutic potential of epigenetic modifiers, few focus on patient data. In addition, in an era of high-throughput technology, it is likely to provide systematical insight and opportunities for effective therapy to combine multi-omics and single-cell sequencing techniques. Ongoing researches on the evolution and application of epigenetic editing therapy in DCM are also needed, which is expected to yield new insights into the pathogenesis and treatment of DCM.

Availability of data and materials

Not applicable.

Abbreviations

α-MHC:

α-myosin heavy chain

ADP:

Adenosine diphosphate

AP:

Activator protein

APA:

Apaberon

BET:

Bromodomain and extra-terminal domain

BRD4:

Bromodomain protein 4

CRISPR:

Clustered regularly interspaced short palindromic repeats

DCM:

Diabetic cardiomyopathy

DNMT:

DNA methyltransferase

ERK:

Extracellular regulated protein kinases

EZH2:

Enhancer of zeste homolog 2

FUS:

Fused in sarcoma

GLUT:

Facilitative glucose transporter

GPX1:

Glutathione peroxidase 1

H3K27ac:

Histone H3 lysine 27 acetylation

H3K27me3:

Trimethylated histone H3 at lysine27

H3K9me3:

Trimethylated histone H3 at lysine9

HATs:

Histone acetyltransferases

HDACs:

Histone deacetylase

HG:

High glucose

HIF:

Hypoxia-inducible factor

IL:

Interleukin

JAK-STAT:

Janus kinase-signal transducer and activator of transcription

lncRNA:

Long non-coding RNA

MAPK:

Mitogen-activated protein kinase

miRNA:

MicroRNAs

ncRNA:

Non-coding RNAs

NF-κB:

Nuclear factor kappa-B

NLRP3:

NOD-like receptor thermal protein domain-associated protein 3

PRC2:

Polycomb repressive complex 2

ROS:

Reactive oxygen species

SERCA2a:

Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a

SIRT:

Sirtuin

SOCS:

Suppressor of cytokine signaling

STZ:

Streptozotocin

TET:

Ten-eleven translocation

TGF-β:

Transforming growth factor beta

UTR:

Untranslated region

References

  1. Teo ZL, Tham YC, Yu M, Chee ML, Rim TH, Cheung N, Bikbov MM, Wang YX, Tang Y, Lu Y, Wong IY, Ting DSW, Tan GSW, Jonas JB, Sabanayagam C, Wong TY, Cheng CY. Global Prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021;128:1580–91.

    Article  PubMed  Google Scholar 

  2. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30:595–602.

    Article  CAS  PubMed  Google Scholar 

  3. Liu D, Xing R, Zhang Q, Tian X, Qi Y, Song H, Liu Y, Yu H, Zhang X, Jing Q, Yan C, Han Y. The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes. Exp Mol Med. 2023;55:2025–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Liu X, Yang ZG, Gao Y, Xie LJ, Jiang L, Hu BY, Diao KY, Shi K, Xu HY, Shen MT, Ren Y, Guo YK. Left ventricular subclinical myocardial dysfunction in uncomplicated type 2 diabetes mellitus is associated with impaired myocardial perfusion: a contrast-enhanced cardiovascular magnetic resonance study. Cardiovasc Diabetol. 2018;17:139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fedeli U, Schievano E, Targher G, Bonora E, Corti MC, Zoppini G. Estimating the real burden of cardiovascular mortality in diabetes. Eur Rev Med Pharmacol Sci. 2019;23:6700–6.

    CAS  PubMed  Google Scholar 

  6. Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 2016;12:144–53.

    Article  CAS  PubMed  Google Scholar 

  7. Elbatreek MH, Pachado MP, Cuadrado A, Jandeleit-Dahm K, Schmidt H. Reactive oxygen comes of age: mechanism-based therapy of diabetic end-organ damage. Trends Endocrinol Metab. 2019;30:312–27.

    Article  CAS  PubMed  Google Scholar 

  8. Tong M, Saito T, Zhai P, Oka SI, Mizushima W, Nakamura M, Ikeda S, Shirakabe A, Sadoshima J. Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy. Circ Res. 2019;124:1360–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang J, Qian C, Chen Y, Jin T, Jiang Y, Huang L, Fu X, Yang D, Jin L, Jin B, Wang Y. β-elemene alleviates hyperglycemia-induced cardiac inflammation and remodeling by inhibiting the JAK/STAT3-NF-κB pathway. Phytomedicine. 2023;119: 154987.

    Article  CAS  PubMed  Google Scholar 

  10. Nacev BA, Jones KB, Intlekofer AM, Yu JSE, Allis CD, Tap WD, Ladanyi M, Nielsen TO. The epigenomics of sarcoma. Nat Rev Cancer. 2020;20:608–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Waddington CH. The epigenotype. Int J Epidemiol. 1942;2012(41):10–3.

    Google Scholar 

  12. Scarano E, Iaccarino M, Grippo P, Winckelmans D. On methylation of DNA during development of the sea urchin embryo. J Mol Biol. 1965;14:603–7.

    Article  CAS  PubMed  Google Scholar 

  13. Maksimovic J, Oshlack A, Phipson B. Gene set enrichment analysis for genome-wide DNA methylation data. Genome Biol. 2021;22:173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Weinberg DN, Papillon-Cavanagh S, Chen H, Yue Y, Chen X, Rajagopalan KN, Horth C, McGuire JT, Xu X, Nikbakht H, Lemiesz AE, Marchione DM, Marunde MR, Meiners MJ, Cheek MA, Keogh MC, Bareke E, Djedid A, Harutyunyan AS, Jabado N, Garcia BA, Li H, Allis CD, Majewski J, Lu C. The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. Nature. 2019;573:281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee DD, Leão R, Komosa M, Gallo M, Zhang CH, Lipman T, Remke M, Heidari A, Nunes NM, Apolónio JD, Price AJ, De Mello RA, Dias JS, Huntsman D, Hermanns T, Wild PJ, Vanner R, Zadeh G, Karamchandani J, Das S, Taylor MD, Hawkins CE, Wasserman JD, Figueiredo A, Hamilton RJ, Minden MD, Wani K, Diplas B, Yan H, Aldape K, Akbari MR, Danesh A, Pugh TJ, Dirks PB, Castelo-Branco P, Tabori U. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer. J Clin Invest. 2019;129:223–9.

    Article  PubMed  Google Scholar 

  16. Zhu H, Wang G, Qian J. Transcription factors as readers and effectors of DNA methylation. Nat Rev Genet. 2016;17:551–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Min B, Park JS, Jeong YS, Jeon K, Kang YK. Dnmt1 binds and represses genomic retroelements via DNA methylation in mouse early embryos. Nucleic Acids Res. 2020;48:8431–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dura M, Teissandier A, Armand M, Barau J, Lapoujade C, Fouchet P, Bonneville L, Schulz M, Weber M, Baudrin LG, Lameiras S, Bourc’his D. DNMT3A-dependent DNA methylation is required for spermatogonial stem cells to commit to spermatogenesis. Nat Genet. 2022;54:469–80.

    Article  CAS  PubMed  Google Scholar 

  19. Dave J, Jagana V, Janostiak R, Bisserier M. Unraveling the epigenetic landscape of pulmonary arterial hypertension: implications for personalized medicine development. J Transl Med. 2023;21:477.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Han P, Li W, Yang J, Shang C, Lin CH, Cheng W, Hang CT, Cheng HL, Chen CH, Wong J, Xiong Y, Zhao M, Drakos SG, Ghetti A, Li DY, Bernstein D, Chen HS, Quertermous T, Chang CP. Epigenetic response to environmental stress: assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts. Biochim Biophys Acta. 2016;1863:1772–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sano S, Oshima K, Wang Y, Katanasaka Y, Sano M, Walsh K. CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. Circ Res. 2018;123:335–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lan Y, Banks KM, Pan H, Verma N, Dixon GR, Zhou T, Ding B, Elemento O, Chen S, Huangfu D, Evans T. Stage-specific regulation of DNA methylation by TET enzymes during human cardiac differentiation. Cell Rep. 2021;37: 110095.

    Article  CAS  PubMed  Google Scholar 

  23. Li X, Yue X, Pastor WA, Lin L, Georges R, Chavez L, Evans SM, Rao A. Tet proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling. Proc Natl Acad Sci U S A. 2016;113:E8267-e8276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Raisner R, Kharbanda S, Jin L, Jeng E, Chan E, Merchant M, Haverty PM, Bainer R, Cheung T, Arnott D, Flynn EM, Romero FA, Magnuson S, Gascoigne KE. Enhancer activity requires CBP/P300 bromodomain-dependent histone H3K27 acetylation. Cell Rep. 2018;24:1722–9.

    Article  CAS  PubMed  Google Scholar 

  25. Fang Y, Tang Y, Zhang Y, Pan Y, Jia J, Sun Z, Zeng W, Chen J, Yuan Y, Fang D. The H3K36me2 methyltransferase NSD1 modulates H3K27ac at active enhancers to safeguard gene expression. Nucleic Acids Res. 2021;49:6281–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hori Y, Kikuchi K. Chemical tools with fluorescence switches for verifying epigenetic modifications. Acc Chem Res. 2019;52:2849–57.

    Article  CAS  PubMed  Google Scholar 

  27. Scholz B, Schulte JS, Hamer S, Himmler K, Pluteanu F, Seidl MD, Stein J, Wardelmann E, Hammer E, Völker U, Müller FU. HDAC (Histone deacetylase) inhibitor valproic acid attenuates atrial remodeling and delays the onset of atrial fibrillation in mice. Circ Arrhythm Electrophysiol. 2019;12: e007071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang M, Zhang Y, Ren J. Acetylation in cardiovascular diseases: molecular mechanisms and clinical implications. Biochim Biophys Acta Mol Basis Dis. 2020;1866: 165836.

    Article  CAS  PubMed  Google Scholar 

  29. Lecce L, Xu Y, V’Gangula B, Chandel N, Pothula V, Caudrillier A, Santini MP, d’Escamard V, Ceholski DK, Gorski PA, Ma L, Koplev S, Bjørklund MM, Björkegren JL, Boehm M, Bentzon JF, Fuster V, Kim HW, Weintraub NL, Baker AH, Bernstein E, Kovacic JC. Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype. J Clin Invest. 2021. https://doi.org/10.1172/JCI131178.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Li Z, Guo Z, Lan R, Cai S, Lin Z, Li J, Wang J, Li Z, Liu P. The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy. Acta Pharm Sin B. 2021;11:1286–99.

    Article  CAS  PubMed  Google Scholar 

  31. Travers JG, Wennersten SA, Peña B, Bagchi RA, Smith HE, Hirsch RA, Vanderlinden LA, Lin YH, Dobrinskikh E, Demos-Davies KM, Cavasin MA, Mestroni L, Steinkühler C, Lin CY, Houser SR, Woulfe KC, Lam MPY, McKinsey TA. HDAC inhibition reverses preexisting diastolic dysfunction and blocks covert extracellular matrix remodeling. Circulation. 2021;143:1874–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chakraborty R, Ostriker AC, Xie Y, Dave JM, Gamez-Mendez A, Chatterjee P, Abu Y, Valentine J, Lezon-Geyda K, Greif DM, Schulz VP, Gallagher PG, Sessa WC, Hwa J, Martin KA. Histone acetyltransferases p300 and CBP coordinate distinct chromatin remodeling programs in vascular smooth muscle plasticity. Circulation. 2022;145:1720–37.

    Article  CAS  PubMed  Google Scholar 

  33. Farina FM, Serio S, Hall IF, Zani S, Cassanmagnago GA, Climent M, Civilini E, Condorelli G, Quintavalle M, Elia L. The epigenetic enzyme DOT1L orchestrates vascular smooth muscle cell-monocyte crosstalk and protects against atherosclerosis via the NF-κB pathway. Eur Heart J. 2022;43:4562–76.

    Article  CAS  PubMed  Google Scholar 

  34. Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol. 2020;13:104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kook H, Seo SB, Jain R. EZ switch from EZH2 to EZH1: histone methylation opens a window of cardiac regeneration. Circ Res. 2017;121:91–4.

    Article  CAS  PubMed  Google Scholar 

  36. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.

    Article  Google Scholar 

  37. Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172:393–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S, Chang HY. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, Kong R, Xia R, Lu KH, Li JH, De W, Wang KM, Wang ZX. Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 2014;13:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Meng F, Li Z, Zhang Z, Yang Z, Kang Y, Zhao X, Long D, Hu S, Gu M, He S, Wu P, Chang Z, He A, Liao W. MicroRNA-193b-3p regulates chondrogenesis and chondrocyte metabolism by targeting HDAC3. Theranostics. 2018;8:2862–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li Y, He Q, Wen X, Hong X, Yang X, Tang X, Zhang P, Lei Y, Sun Y, Zhang J, Wang Y, Ma J, Liu N. EZH2-DNMT1-mediated epigenetic silencing of miR-142-3p promotes metastasis through targeting ZEB2 in nasopharyngeal carcinoma. Cell Death Differ. 2019;26:1089–106.

    Article  CAS  PubMed  Google Scholar 

  42. Hathaway QA, Roth SM, Pinti MV, Sprando DC, Kunovac A, Durr AJ, Cook CC, Fink GK, Cheuvront TB, Grossman JH, Aljahli GA, Taylor AD, Giromini AP, Allen JL, Hollander JM. Machine-learning to stratify diabetic patients using novel cardiac biomarkers and integrative genomics. Cardiovasc Diabetol. 2019;18:78.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Costantino S, Akhmedov A, Melina G, Mohammed SA, Othman A, Ambrosini S, Wijnen WJ, Sada L, Ciavarella GM, Liberale L, Tanner FC, Matter CM, Hornemann T, Volpe M, Mechta-Grigoriou F, Camici GG, Sinatra R, Lüscher TF, Paneni F. Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy. Eur Heart J. 2019;40:997–1008.

    Article  CAS  PubMed  Google Scholar 

  44. Marfella R, D’Onofrio N, Trotta MC, Sardu C, Scisciola L, Amarelli C, Balestrieri ML, Grimaldi V, Mansueto G, Esposito S, D’Amico M, Golino P, Signoriello G, De Feo M, Maiello C, Napoli C, Paolisso G. Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts. Metabolism. 2022;127: 154936.

    Article  CAS  PubMed  Google Scholar 

  45. Hussain S, Khan AW, Akhmedov A, Suades R, Costantino S, Paneni F, Caidahl K, Mohammed SA, Hage C, Gkolfos C, Björck H, Pernow J, Lund LH, Lüscher TF, Cosentino F. Hyperglycemia induces myocardial dysfunction via epigenetic regulation of JunD. Circ Res. 2020;127:1261–73.

    Article  CAS  PubMed  Google Scholar 

  46. Torre E, Arici M, Lodrini AM, Ferrandi M, Barassi P, Hsu SC, Chang GJ, Boz E, Sala E, Vagni S, Altomare C, Mostacciuolo G, Bussadori C, Ferrari P, Bianchi G, Rocchetti M. SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy. Cardiovasc Res. 2022;118:1020–32.

    Article  CAS  PubMed  Google Scholar 

  47. Peng S, Wang M, Zhang S, Liu N, Li Q, Kang J, Chen L, Li M, Pang K, Huang J, Lu F, Zhao D, Zhang W. Hydrogen sulfide regulates SERCA2a SUMOylation by S-Sulfhydration of SENP1 to ameliorate cardiac systole-diastole function in diabetic cardiomyopathy. Biomed Pharmacother. 2023;160: 114200.

    Article  CAS  PubMed  Google Scholar 

  48. Sultan CS, Saackel A, Stank A, Fleming T, Fedorova M, Hoffmann R, Wade RC, Hecker M, Wagner AH. Impact of carbonylation on glutathione peroxidase-1 activity in human hyperglycemic endothelial cells. Redox Biol. 2018;16:113–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yun Y, Zhang Y, Li G, Chen S, Sang N. Embryonic exposure to oxy-polycyclic aromatic hydrocarbon interfere with pancreatic β-cell development in zebrafish via altering DNA methylation and gene expression. Sci Total Environ. 2019;660:1602–9.

    Article  CAS  PubMed  Google Scholar 

  50. Zhu H, Wang X, Meng X, Kong Y, Li Y, Yang C, Guo Y, Wang X, Yang H, Liu Z, Wang F. Selenium supplementation improved cardiac functions by suppressing DNMT2-mediated GPX1 promoter DNA methylation in AGE-induced heart failure. Oxid Med Cell Longev. 2022;2022:5402997.

    PubMed  PubMed Central  Google Scholar 

  51. Wang S, Zha L, Cui X, Yeh YT, Liu R, Jing J, Shi H, Chen W, Hanover J, Yin J, Yu L, Xue B, Shi H. Epigenetic regulation of hepatic lipid metabolism by DNA methylation. Adv Sci (Weinh). 2023;10: e2206068.

    Article  PubMed  Google Scholar 

  52. Kakoki M, Ramanathan PV, Hagaman JR, Grant R, Wilder JC, Taylor JM, Charles Jennette J, Smithies O, Maeda-Smithies N. Cyanocobalamin prevents cardiomyopathy in type 1 diabetes by modulating oxidative stress and DNMT-SOCS1/3-IGF-1 signaling. Commun Biol. 2021;4:775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Shuai J, Gao Y, Chen L, Wang Z. Role of serotonin in regulation of pancreatic and mesenteric arterial function in diabetic mice. Eur J Pharmacol. 2021;901: 174070.

    Article  CAS  PubMed  Google Scholar 

  54. Guo Y, Zou J, Xu X, Zhou H, Sun X, Wu L, Zhang S, Zhong X, Xiong Z, Lin Y, Huang Y, Du Z, Liao X, Zhuang X. Short-chain fatty acids combined with intronic DNA methylation of HIF3A: potential predictors for diabetic cardiomyopathy. Clin Nutr. 2021;40:3708–17.

    Article  CAS  PubMed  Google Scholar 

  55. Li P, Ge J, Li H. Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease. Nat Rev Cardiol. 2020;17:96–115.

    Article  CAS  PubMed  Google Scholar 

  56. Song S, Ding Y, Dai GL, Zhang Y, Xu MT, Shen JR, Chen TT, Chen Y, Meng GL. Sirtuin 3 deficiency exacerbates diabetic cardiomyopathy via necroptosis enhancement and NLRP3 activation. Acta Pharmacol Sin. 2021;42:230–41.

    Article  CAS  PubMed  Google Scholar 

  57. Yu LM, Dong X, Xue XD, Xu S, Zhang X, Xu YL, Wang ZS, Wang Y, Gao H, Liang YX, Yang Y, Wang HS. Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia-reperfusion injury by improving mitochondrial quality control: role of SIRT6. J Pineal Res. 2021;70: e12698.

    Article  CAS  PubMed  Google Scholar 

  58. Jin L, Geng L, Ying L, Shu L, Ye K, Yang R, Liu Y, Wang Y, Cai Y, Jiang X, Wang Q, Yan X, Liao B, Liu J, Duan F, Sweeney G, Woo CWH, Wang Y, Xia Z, Lian Q, Xu A. FGF21-sirtuin 3 axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity. Circulation. 2022;146:1537–57.

    Article  CAS  PubMed  Google Scholar 

  59. Palomer X, Aguilar-Recarte D, García R, Nistal JF, Vázquez-Carrera M. Sirtuins: to be or not to be in diabetic cardiomyopathy. Trends Mol Med. 2021;27:554–71.

    Article  CAS  PubMed  Google Scholar 

  60. Cappelluti MA, Mollica Poeta V, Valsoni S, Quarato P, Merlin S, Merelli I, Lombardo A. Durable and efficient gene silencing in vivo by hit-and-run epigenome editing. Nature. 2024;627(8003):416–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chen Y, Du J, Zhao YT, Zhang L, Lv G, Zhuang S, Qin G, Zhao TC. Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc Diabetol. 2015;14:99.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Xu Z, Tong Q, Zhang Z, Wang S, Zheng Y, Liu Q, Qian LB, Chen SY, Sun J, Cai L. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin Sci (Lond). 2017;131:1841–57.

    Article  CAS  PubMed  Google Scholar 

  63. Brasacchio D, Okabe J, Tikellis C, Balcerczyk A, George P, Baker EK, Calkin AC, Brownlee M, Cooper ME, El-Osta A. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes. 2009;58:1229–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Vecellio M, Spallotta F, Nanni S, Colussi C, Cencioni C, Derlet A, Bassetti B, Tilenni M, Carena MC, Farsetti A, Sbardella G, Castellano S, Mai A, Martelli F, Pompilio G, Capogrossi MC, Rossini A, Dimmeler S, Zeiher A, Gaetano C. The histone acetylase activator pentadecylidenemalonate 1b rescues proliferation and differentiation in the human cardiac mesenchymal cells of type 2 diabetic patients. Diabetes. 2014;63:2132–47.

    Article  CAS  PubMed  Google Scholar 

  65. Huang G, Cheng Z, Hildebrand A, Wang C, Cimini M, Roy R, Lucchese AM, Benedict C, Mallaredy V, Magadum A, Joladarashi D, Thej C, Gonzalez C, Trungcao M, Garikipati VNS, Elrod JW, Koch WJ, Kishore R. Diabetes impairs cardioprotective function of endothelial progenitor cell-derived extracellular vesicles via H3K9Ac inhibition. Theranostics. 2022;12:4415–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kozuka C, Efthymiou V, Sales VM, Zhou L, Osataphan S, Yuchi Y, Chimene-Weiss J, Mulla C, Isganaitis E, Desmond J, Sanechika S, Kusuyama J, Goodyear L, Shi X, Gerszten RE, Aguayo-Mazzucato C, Carapeto P, Teixeira SD, Sandoval D, Alonso-Curbelo D, Wu L, Qi J, Patti ME. Bromodomain inhibition reveals FGF15/19 as a target of epigenetic regulation and metabolic control. Diabetes. 2022;71:1023–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim SY, Zhang X, Schiattarella GG, Altamirano F, Ramos TAR, French KM, Jiang N, Szweda PA, Evers BM, May HI, Luo X, Li H, Szweda LI, Maracaja-Coutinho V, Lavandero S, Gillette TG, Hill JA. Epigenetic reader BRD4 (bromodomain-containing protein 4) governs nucleus-encoded mitochondrial transcriptome to regulate cardiac function. Circulation. 2020;142:2356–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nord JA, Wynia-Smith SL, Gehant AL, Jones Lipinski RA, Naatz A, Rioja I, Prinjha RK, Corbett JA, Smith BC. N-terminal BET bromodomain inhibitors disrupt a BRD4-p65 interaction and reduce inducible nitric oxide synthase transcription in pancreatic β-cells. Front Endocrinol (Lausanne). 2022;13: 923925.

    Article  PubMed  Google Scholar 

  69. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fan M, Yang K, Wang X, Chen L, Gill PS, Ha T, Liu L, Lewis NH, Williams DL, Li C. Lactate promotes endothelial-to-mesenchymal transition via Snail1 lactylation after myocardial infarction. Sci Adv. 2023;9:eadc9465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fang X, Zhao P, Gao S, Liu D, Zhang S, Shan M, Wang Y, Herrmann J, Li Q, Wang F. Lactate induces tumor-associated macrophage polarization independent of mitochondrial pyruvate carrier-mediated metabolism. Int J Biol Macromol. 2023;237: 123810.

    Article  CAS  PubMed  Google Scholar 

  72. Wang N, Wang W, Wang X, Mang G, Chen J, Yan X, Tong Z, Yang Q, Wang M, Chen L, Sun P, Yang Y, Cui J, Yang M, Zhang Y, Wang D, Wu J, Zhang M, Yu B. Histone lactylation boosts reparative gene activation post-myocardial infarction. Circ Res. 2022;131:893–908.

    Article  CAS  PubMed  Google Scholar 

  73. Zhang N, Zhang Y, Xu J, Wang P, Wu B, Lu S, Lu X, You S, Huang X, Li M, Zou Y, Liu M, Zhao Y, Sun G, Wang W, Geng D, Liu J, Cao L, Sun Y. α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure. Cell Res. 2023;33:679–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Moreno-Yruela C, Zhang D, Wei W, Bæk M, Liu W, Gao J, Danková D, Nielsen AL, Bolding JE, Yang L, Jameson ST, Wong J, Olsen CA, Zhao Y. Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci Adv. 2022;8:eabi6696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res. 2018;122:624–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Abais JM, Xia M, Zhang Y, Boini KM, Li PL. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal. 2015;22:1111–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Qin Y, Li Q, Liang W, Yan R, Tong L, Jia M, Zhao C, Zhao W. TRIM28 SUMOylates and stabilizes NLRP3 to facilitate inflammasome activation. Nat Commun. 2021;12:4794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Meng L, Lin H, Huang X, Weng J, Peng F, Wu S. METTL14 suppresses pyroptosis and diabetic cardiomyopathy by downregulating TINCR lncRNA. Cell Death Dis. 2022;13:38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Abo-Saif MA, Ragab AE, Ibrahim AO, Abdelzaher OF, Mehanyd ABM, Saber-Ayad M, El-Feky OA. Pomegranate peel extract protects against the development of diabetic cardiomyopathy in rats by inhibiting pyroptosis and downregulating LncRNA-MALAT1. Front Pharmacol. 2023;14:1166653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chen T, Meng Y, Zhou Z, Li H, Wan L, Kang A, Guo W, Ren K, Song X, Chen Y, Zhao W. GAS5 protects against nonalcoholic fatty liver disease via miR-28a-5p/MARCH7/NLRP3 axis-mediated pyroptosis. Cell Death Differ. 2023;30:1829–48.

    Article  CAS  PubMed  Google Scholar 

  81. Xu Y, Fang H, Xu Q, Xu C, Yang L, Huang C. LncRNA GAS5 inhibits NLRP3 inflammasome activation-mediated pyroptosis in diabetic cardiomyopathy by targeting miR-34b-3p/AHR. Cell Cycle. 2020;19:3054–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yang F, Qin Y, Lv J, Wang Y, Che H, Chen X, Jiang Y, Li A, Sun X, Yue E, Ren L, Li Y, Bai Y, Wang L. Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis. 2018;9:1000.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Zhang Y, Zhang YY, Li TT, Wang J, Jiang Y, Zhao Y, Jin XX, Xue GL, Yang Y, Zhang XF, Sun YY, Zhang ZR, Gao X, Du ZM, Lu YJ, Yang BF, Pan ZW. Ablation of interleukin-17 alleviated cardiac interstitial fibrosis and improved cardiac function via inhibiting long non-coding RNA-AK081284 in diabetic mice. J Mol Cell Cardiol. 2018;115:64–72.

    Article  PubMed  Google Scholar 

  84. Zheng D, Zhang Y, Hu Y, Guan J, Xu L, Xiao W, Zhong Q, Ren C, Lu J, Liang J, Hou J. Long noncoding RNA Crnde attenuates cardiac fibrosis via Smad3-Crnde negative feedback in diabetic cardiomyopathy. Febs j. 2019;286:1645–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Xiong J, Zhou Q. The lncRNA HOTAIR attenuates pyroptosis of diabetic cardiomyocytes by recruiting FUS to regulate SIRT3 expression. Kaohsiung J Med Sci. 2023;39:458–67.

    Article  CAS  PubMed  Google Scholar 

  86. Gao L, Wang X, Guo S, Xiao L, Liang C, Wang Z, Li Y, Liu Y, Yao R, Liu Y, Zhang Y. LncRNA HOTAIR functions as a competing endogenous RNA to upregulate SIRT1 by sponging miR-34a in diabetic cardiomyopathy. J Cell Physiol. 2019;234:4944–58.

    Article  CAS  PubMed  Google Scholar 

  87. Li X, Wang H, Yao B, Xu W, Chen J, Zhou X. lncRNA H19/miR-675 axis regulates cardiomyocyte apoptosis by targeting VDAC1 in diabetic cardiomyopathy. Sci Rep. 2016;6:36340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tang H, Zhong H, Liu W, Wang Y, Wang Y, Wang L, Tang S, Zhu H. Melatonin alleviates hyperglycemia-induced cardiomyocyte apoptosis via regulation of long non-coding RNA H19/miR-29c/MAPK axis in diabetic cardiomyopathy. Pharmaceuticals (Basel). 2022;15(7):821.

    Article  CAS  PubMed  Google Scholar 

  89. Costantino S, Paneni F, Lüscher TF, Cosentino F. MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart. Eur Heart J. 2016;37:572–6.

    Article  CAS  PubMed  Google Scholar 

  90. Liu S, Li W, Xu M, Huang H, Wang J, Chen X. Micro-RNA 21Targets dual specific phosphatase 8 to promote collagen synthesis in high glucose-treated primary cardiac fibroblasts. Can J Cardiol. 2014;30:1689–99.

    Article  PubMed  Google Scholar 

  91. Kambis TN, Shahshahan HR, Kar S, Yadav SK, Mishra PK. Transgenic expression of miR-133a in the diabetic akita heart prevents cardiac remodeling and cardiomyopathy. Front Cardiovasc Med. 2019;6:45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nandi SS, Zheng H, Sharma NM, Shahshahan HR, Patel KP, Mishra PK. Lack of miR-133a decreases contractility of diabetic hearts: a role for novel cross talk between tyrosine aminotransferase and tyrosine hydroxylase. Diabetes. 2016;65:3075–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Li X, Meng C, Han F, Yang J, Wang J, Zhu Y, Cui X, Zuo M, Xu J, Chang B. Vildagliptin attenuates myocardial dysfunction and restores autophagy via miR-21/SPRY1/ERK in diabetic mice heart. Front Pharmacol. 2021;12: 634365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li H, Yang Q, Huang Z, Liang C, Zhang DH, Shi HT, Du JQ, Du BB, Zhang YZ. Dual-specificity phosphatase 12 attenuates oxidative stress injury and apoptosis in diabetic cardiomyopathy via the ASK1-JNK/p38 signaling pathway. Free Radic Biol Med. 2022;192:13–24.

    Article  CAS  PubMed  Google Scholar 

  95. Li H, Fan J, Zhao Y, Zhang X, Dai B, Zhan J, Yin Z, Nie X, Fu XD, Chen C, Wang DW. Nuclear miR-320 mediates diabetes-induced cardiac dysfunction by activating transcription of fatty acid metabolic genes to cause lipotoxicity in the heart. Circ Res. 2019;125:1106–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hu S, Chen L, Zeng T, Wang W, Yan Y, Qiu K, Xie Y, Liao Y. DNA methylation profiling reveals novel pathway implicated in cardiovascular diseases of diabetes. Front Endocrinol (Lausanne). 2023;14:1108126.

    Article  PubMed  Google Scholar 

  97. Topriceanu CC, Dev E, Ahmad M, Hughes R, Shiwani H, Webber M, Direk K, Wong A, Ugander M, Moon JC, Hughes AD, Maddock J, Schlegel TT, Captur G. Accelerated DNA methylation age plays a role in the impact of cardiovascular risk factors on the human heart. Clin Epigenetics. 2023;15:164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gadd DA, Hillary RF, McCartney DL, Zaghlool SB, Stevenson AJ, Cheng Y, Fawns-Ritchie C, Nangle C, Campbell A, Flaig R, Harris SE, Walker RM, Shi L, Tucker-Drob EM, Gieger C, Peters A, Waldenberger M, Graumann J, McRae AF, Deary IJ, Porteous DJ, Hayward C, Visscher PM, Cox SR, Evans KL, McIntosh AM, Suhre K, Marioni RE. Epigenetic scores for the circulating proteome as tools for disease prediction. Elife. 2022. https://doi.org/10.7554/eLife.71802.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Jin ZQ. MicroRNA targets and biomarker validation for diabetes-associated cardiac fibrosis. Pharmacol Res. 2021;174: 105941.

    Article  CAS  PubMed  Google Scholar 

  100. Bielska A, Niemira M, Bauer W, Sidorkiewicz I, Szałkowska A, Skwarska A, Raczkowska J, Ostrowski D, Gugała K, Dobrzycki S, Krętowski A. Serum miRNA profile in diabetic patients with ischemic heart disease as a promising non-invasive biomarker. Front Endocrinol (Lausanne). 2022;13: 888948.

    Article  PubMed  Google Scholar 

  101. Pofi R, Giannetta E, Galea N, Francone M, Campolo F, Barbagallo F, Gianfrilli D, Venneri MA, Filardi T, Cristini C, Antonini G, Badagliacca R, Frati G, Lenzi A, Carbone I, Isidori AM. Diabetic cardiomiopathy progression is triggered by miR122-5p and involves extracellular matrix: a 5-year prospective study. JACC Cardiovasc Imaging. 2021;14:1130–42.

    Article  PubMed  Google Scholar 

  102. García-Calzón S, Perfilyev A, Martinell M, Ustinova M, Kalamajski S, Franks PW, Bacos K, Elbere I, Pihlajamäki J, Volkov P, Vaag A, Groop L, Maziarz M, Klovins J, Ahlqvist E, Ling C. Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes. Sci Transl Med. 2020. https://doi.org/10.1126/scitranslmed.aaz1803.

    Article  PubMed  Google Scholar 

  103. Mu J, Zhang D, Tian Y, Xie Z, Zou MH. BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo. J Mol Cell Cardiol. 2020;149:1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ray KK, Nicholls SJ, Buhr KA, Ginsberg HN, Johansson JO, Kalantar-Zadeh K, Kulikowski E, Toth PP, Wong N, Sweeney M, Schwartz GG. Effect of apabetalone added to standard therapy on major adverse cardiovascular events in patients with recent acute coronary syndrome and type 2 diabetes: a randomized clinical trial. JAMA. 2020;323:1565–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Singh R, Ha SE, Wei L, Jin B, Zogg H, Poudrier SM, Jorgensen BG, Park C, Ronkon CF, Bartlett A, Cho S, Morales A, Chung YH, Lee MY, Park JK, Gottfried-Blackmore A, Nguyen L, Sanders KM, Ro S. miR-10b-5p rescues diabetes and gastrointestinal dysmotility. Gastroenterology. 2021;160:1662-1678.e18.

    Article  CAS  PubMed  Google Scholar 

  106. Manghwar H, Lindsey K, Zhang X, Jin S. CRISPR/Cas system: recent advances and future prospects for genome editing. Trends Plant Sci. 2019;24:1102–25.

    Article  CAS  PubMed  Google Scholar 

  107. Bhat AA, Nisar S, Mukherjee S, Saha N, Yarravarapu N, Lone SN, Masoodi T, Chauhan R, Maacha S, Bagga P, Dhawan P, Akil AA, El-Rifai W, Uddin S, Reddy R, Singh M, Macha MA, Haris M. Integration of CRISPR/Cas9 with artificial intelligence for improved cancer therapeutics. J Transl Med. 2022;20:534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ou K, Yu M, Moss NG, Wang YJ, Wang AW, Nguyen SC, Jiang C, Feleke E, Kameswaran V, Joyce EF, Naji A, Glaser B, Avrahami D, Kaestner KH. Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication. J Clin Invest. 2019;129:209–14.

    Article  PubMed  Google Scholar 

  109. Matboli M, Kamel MM, Essawy N, Bekhit MM, Abdulrahman B, Mohamed GF, Eissa S. Identification of novel insulin resistance related ceRNA network in T2DM and its potential editing by CRISPR/Cas9. Int J Mol Sci. 2021;22(15):8129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Feng Y, Xu W, Zhang W, Wang W, Liu T, Zhou X. LncRNA DCRF regulates cardiomyocyte autophagy by targeting miR-551b-5p in diabetic cardiomyopathy. Theranostics. 2019;9:4558–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhang Q, Li D, Dong X, Zhang X, Liu J, Peng L, Meng B, Hua Q, Pei X, Zhao L, Hu X, Zhang Y, Pan Z, Lu Y, Yang B. LncDACH1 promotes mitochondrial oxidative stress of cardiomyocytes by interacting with sirtuin3 and aggravates diabetic cardiomyopathy. Sci China Life Sci. 2022;65:1198–212.

    Article  CAS  PubMed  Google Scholar 

  112. Zhao SF, Ye YX, Xu JD, He Y, Zhang DW, Xia ZY, Wang S. Long non-coding RNA KCNQ1OT1 increases the expression of PDCD4 by targeting miR-181a-5p, contributing to cardiomyocyte apoptosis in diabetic cardiomyopathy. Acta Diabetol. 2021;58:1251–67.

    Article  CAS  PubMed  Google Scholar 

  113. Xie R, Fan J, Wen J, Jin K, Zhan J, Yuan S, Tang Y, Nie X, Wen Z, Li H, Chen C, Wang DW. LncRNA ZNF593-AS alleviates diabetic cardiomyopathy via suppressing IRF3 signaling pathway. Mol Ther Nucleic Acids. 2023;32:689–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhang M, Gu H, Chen J, Zhou X. Involvement of long noncoding RNA MALAT1 in the pathogenesis of diabetic cardiomyopathy. Int J Cardiol. 2016;202:753–5.

    Article  PubMed  Google Scholar 

  115. Shi C, Wu L, Li L. LncRNA-MALAT 1 regulates cardiomyocyte scorching in diabetic cardiomyopathy by targeting NLRP3. Cell Mol Biol Noisy-le-grand. 2022;67:213–9.

    Article  PubMed  Google Scholar 

  116. Pei C, Gong X, Zhang Y. LncRNA MALAT-1 promotes growth and metastasis of epithelial ovarian cancer via sponging microrna-22. Am J Transl Res. 2020;12:6977–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Zhang M, Gu H, Xu W, Zhou X. Down-regulation of lncRNA MALAT1 reduces cardiomyocyte apoptosis and improves left ventricular function in diabetic rats. Int J Cardiol. 2016;203:214–6.

    Article  PubMed  Google Scholar 

  118. Peng T, Liu M, Hu L, Guo D, Wang D, Qi B, Ren G, Hu C, Zhang F, Chun HJ, Song L, Hu J, Li Y. LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis. Biol Direct. 2022;17:32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ni T, Huang X, Pan S, Lu Z. Inhibition of the long non-coding RNA ZFAS1 attenuates ferroptosis by sponging miR-150-5p and activates CCND2 against diabetic cardiomyopathy. J Cell Mol Med. 2021;25:9995–10007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Su D, Ju Y, Han W, Yang Y, Wang F, Wang T, Tang J. Tcf3-activated lncRNA Gas5 regulates newborn mouse cardiomyocyte apoptosis in diabetic cardiomyopathy. J Cell Biochem. 2020;121:4337–46.

    Article  CAS  PubMed  Google Scholar 

  121. Chen D, Zhang M. GAS5 regulates diabetic cardiomyopathy via miR-221-3p/p27 axis-associated autophagy. Mol Med Rep. 2021;23(2):1.

    Google Scholar 

  122. Zhuo X, Bai K, Wang Y, Liu P, Xi W, She J, Liu J. Long-chain noncoding RNA-GAS5/hsa-miR-138–5p attenuates high glucose-induced cardiomyocyte damage by targeting CYP11B2. Biosci Rep. 2021;41(9):BSR20202232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chen Y, Tan S, Liu M, Li J. LncRNA TINCR is downregulated in diabetic cardiomyopathy and relates to cardiomyocyte apoptosis. Scand Cardiovasc J. 2018;52:335–9.

    Article  CAS  PubMed  Google Scholar 

  124. Qin W, Zhao X, Tai J, Qin G, Yu S. Combination of dendrobium mixture and metformin curbs the development and progression of diabetic cardiomyopathy by targeting the lncRNA NEAT1. Clinics (Sao Paulo). 2021;76: e2669.

    Article  PubMed  Google Scholar 

  125. Zhou X, Zhang W, Jin M, Chen J, Xu W, Kong X. lncRNA MIAT functions as a competing endogenous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathy. Cell Death Dis. 2017;8: e2929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Liu Y, Zhu Y, Liu S, Liu J, Li X. NORAD lentivirus shRNA mitigates fibrosis and inflammatory responses in diabetic cardiomyopathy via the ceRNA network of NORAD/miR-125a-3p/Fyn. Inflamm Res. 2021;70:1113–27.

    Article  CAS  PubMed  Google Scholar 

  127. Dai W, Lee D. Interfering with long chain noncoding RNA ANRIL expression reduces heart failure in rats with diabetes by inhibiting myocardial oxidative stress. J Cell Biochem. 2019;120:18446–56.

    Article  CAS  PubMed  Google Scholar 

  128. Yu M, Shan X, Liu Y, Zhu J, Cao Q, Yang F, Liu Y, Wang G, Zhao X. RNA-Seq analysis and functional characterization revealed lncRNA NONRATT007560.2 regulated cardiomyocytes oxidative stress and apoptosis induced by high glucose. J Cell Biochem. 2019;120:18278–87.

    Article  CAS  PubMed  Google Scholar 

  129. Chen Y, Zhang Z, Zhu D, Zhao W, Li F. Long non-coding RNA MEG3 serves as a ceRNA for microRNA-145 to induce apoptosis of AC16 cardiomyocytes under high glucose condition. 2019. Biosci Rep. https://doi.org/10.1042/BSR20190444.

  130. Yu FR, Xia YW, Wang SB, Xiao LH. Long noncoding RNA PVT1 facilitates high glucose-induced cardiomyocyte death through the miR-23a-3p/CASP10 axis. Cell Biol Int. 2021;45:154–63.

    Article  PubMed  Google Scholar 

  131. Xing R, Liu D, Cheng X, Tian X, Yan C, Han Y. MiR-207 inhibits autophagy and promotes apoptosis of cardiomyocytes by directly targeting LAMP2 in type 2 diabetic cardiomyopathy. Biochem Biophys Res Commun. 2019;520:27–34.

    Article  CAS  PubMed  Google Scholar 

  132. Li X, Du N, Zhang Q, Li J, Chen X, Liu X, Hu Y, Qin W, Shen N, Xu C, Fang Z, Wei Y, Wang R, Du Z, Zhang Y, Lu Y. MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy. Cell Death Dis. 2014;5: e1479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zhang WY, Wang J, Li AZ. A study of the effects of SGLT-2 inhibitors on diabetic cardiomyopathy through miR-30d/KLF9/VEGFA pathway. Eur Rev Med Pharmacol Sci. 2020;24:6346–59.

    PubMed  Google Scholar 

  134. Xu D, Zhang X, Chen X, Yang S, Chen H. Inhibition of miR-223 attenuates the NLRP3 inflammasome activation, fibrosis, and apoptosis in diabetic cardiomyopathy. Life Sci. 2020;256: 117980.

    Article  CAS  PubMed  Google Scholar 

  135. Lu H, Buchan RJ, Cook SA. MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. Cardiovasc Res. 2010;86:410–20.

    Article  CAS  PubMed  Google Scholar 

  136. Zhang Y, Wang JH, Zhang YY, Wang YZ, Wang J, Zhao Y, Jin XX, Xue GL, Li PH, Sun YL, Huang QH, Song XT, Zhang ZR, Gao X, Yang BF, Du ZM, Pan ZW. Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFβ1 and miR-29 pathways. Sci Rep. 2016;6:23010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Che H, Wang Y, Li Y, Lv J, Li H, Liu Y, Dong R, Sun Y, Xu X, Zhao J, Wang L. Inhibition of microRNA-150-5p alleviates cardiac inflammation and fibrosis via targeting Smad7 in high glucose-treated cardiac fibroblasts. J Cell Physiol. 2020;235:7769–79.

    Article  CAS  PubMed  Google Scholar 

  138. Kuwabara Y, Horie T, Baba O, Watanabe S, Nishiga M, Usami S, Izuhara M, Nakao T, Nishino T, Otsu K, Kita T, Kimura T, Ono K. MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. Circ Res. 2015;116:279–88.

    Article  CAS  PubMed  Google Scholar 

  139. Zheng D, Ma J, Yu Y, Li M, Ni R, Wang G, Chen R, Li J, Fan GC, Lacefield JC, Peng T. Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice. Diabetologia. 2015;58:1949–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Miao Y, Wan Q, Liu X, Wang Y, Luo Y, Liu D, Lin N, Zhou H, Zhong J. miR-503 is involved in the protective effect of phase II enzyme inducer (CPDT) in diabetic cardiomyopathy via Nrf2/ARE signaling pathway. Biomed Res Int. 2017;2017:9167450.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Lin H, Chen X, Pan J, Ke J, Zhang A, Liu Y, Wang C, Chang ACY, Gu J. Secretion of miRNA-326-3p by senescent adipose exacerbates myocardial metabolism in diabetic mice. J Transl Med. 2022;20:278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Chen C, Yang S, Li H, Yin Z, Fan J, Zhao Y, Gong W, Yan M, Wang DW. Mir30c is involved in diabetic cardiomyopathy through regulation of cardiac autophagy via BECN1. Mol Ther Nucleic Acids. 2017;7:127–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Raut SK, Singh GB, Rastogi B, Saikia UN, Mittal A, Dogra N, Singh S, Prasad R, Khullar M. miR-30c and miR-181a synergistically modulate p53–p21 pathway in diabetes induced cardiac hypertrophy. Mol Cell Biochem. 2016;417:191–203.

    Article  CAS  PubMed  Google Scholar 

  144. Raut SK, Kumar A, Singh GB, Nahar U, Sharma V, Mittal A, Sharma R, Khullar M. miR-30c mediates upregulation of Cdc42 and Pak1 in diabetic cardiomyopathy. Cardiovasc Ther. 2015;33:89–97.

    Article  CAS  PubMed  Google Scholar 

  145. Yin Z, Zhao Y, He M, Li H, Fan J, Nie X, Yan M, Chen C, Wang DW. MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα. Cardiovasc Diabetol. 2019;18:7.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Chen S, Puthanveetil P, Feng B, Matkovich SJ, Dorn GW 2nd, Chakrabarti S. Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes. J Cell Mol Med. 2014;18:415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Feng B, Cao Y, Chen S, Chu X, Chu Y, Chakrabarti S. miR-200b mediates endothelial-to-mesenchymal transition in diabetic cardiomyopathy. Diabetes. 2016;65:768–79.

    Article  CAS  PubMed  Google Scholar 

  148. Wang Z, Wang Z, Gao L, Xiao L, Yao R, Du B, Li Y, Wu L, Liang C, Huang Z, Li P, Zhang Y. miR-222 inhibits cardiac fibrosis in diabetic mice heart via regulating Wnt/β-catenin-mediated endothelium to mesenchymal transition. J Cell Physiol. 2020;235:2149–60.

    Article  CAS  PubMed  Google Scholar 

  149. Yildirim SS, Akman D, Catalucci D, Turan B. Relationship between downregulation of miRNAs and increase of oxidative stress in the development of diabetic cardiac dysfunction: junctin as a target protein of miR-1. Cell Biochem Biophys. 2013;67:1397–408.

    Article  CAS  PubMed  Google Scholar 

  150. Jeyabal P, Thandavarayan RA, Joladarashi D, Suresh Babu S, Krishnamurthy S, Bhimaraj A, Youker KA, Kishore R, Krishnamurthy P. MicroRNA-9 inhibits hyperglycemia-induced pyroptosis in human ventricular cardiomyocytes by targeting ELAVL1. Biochem Biophys Res Commun. 2016;471:423–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Yang X, Li X, Lin Q, Xu Q. Up-regulation of microRNA-203 inhibits myocardial fibrosis and oxidative stress in mice with diabetic cardiomyopathy through the inhibition of PI3K/Akt signaling pathway via PIK3CA. Gene. 2019;715: 143995.

    Article  CAS  PubMed  Google Scholar 

  152. Dai B, Li H, Fan J, Zhao Y, Yin Z, Nie X, Wang DW, Chen C. MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin. Cardiovasc Diabetol. 2018;17:123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tang Q, Len Q, Liu Z, Wang W. Overexpression of miR-22 attenuates oxidative stress injury in diabetic cardiomyopathy via Sirt 1. Cardiovasc Ther. 2018;36(2):e12318.

    Article  Google Scholar 

  154. Shen E, Diao X, Wang X, Chen R, Hu B. MicroRNAs involved in the mitogen-activated protein kinase cascades pathway during glucose-induced cardiomyocyte hypertrophy. Am J Pathol. 2011;179:639–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Rawal S, Munasinghe PE, Nagesh PT, Lew JKS, Jones GT, Williams MJA, Davis P, Bunton D, Galvin IF, Manning P, Lamberts RR, Katare R. Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart. Clin Sci (Lond). 2017;131:847–63.

    Article  CAS  PubMed  Google Scholar 

  156. Che H, Wang Y, Li H, Li Y, Sahil A, Lv J, Liu Y, Yang Z, Dong R, Xue H, Wang L. Melatonin alleviates cardiac fibrosis via inhibiting lncRNA MALAT1/miR-141-mediated NLRP3 inflammasome and TGF-β1/Smads signaling in diabetic cardiomyopathy. Faseb j. 2020;34:5282–98.

    Article  CAS  PubMed  Google Scholar 

  157. Feng B, Chen S, Gordon AD, Chakrabarti S. miR-146a mediates inflammatory changes and fibrosis in the heart in diabetes. J Mol Cell Cardiol. 2017;105:70–6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The figures in this review article were created using Adobe Illustrator.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant number: 82170392) and Hubei Key Research and Development Program (No. 2021BCA121).

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China

    Xiaozhu Ma, Shuai Mei, Qidamugai Wuyun, Li Zhou & Jiangtao Yan

  2. Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, China

    Xiaozhu Ma, Shuai Mei, Qidamugai Wuyun, Li Zhou & Jiangtao Yan

  3. Department of Cardiology, Wuhan No. 1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, China

    Dating Sun

  4. Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jiangtao Yan

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XM did conceptualization and writing—original draft preparation; SM and DS visualized the study; SM, Qidamugai Wuyun, LZ, DS and JY supervised the study; JY done funding acquisition. All authors read and approved the final manuscript.

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Ma, X., Mei, S., Wuyun, Q. et al. Epigenetics in diabetic cardiomyopathy. Clin Epigenet 16, 52 (2024). https://doi.org/10.1186/s13148-024-01667-1

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Keywords

Clinical Epigenetics

ISSN: 1868-7083

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