Non‐coding RNA involvement in the pathogenesis of diabetic cardiomyopathy

Abstract In recent years, the incidence of diabetes has been increasing rapidly, which seriously endangers human health. Diabetic cardiomyopathy, an important cardiovascular complication of diabetes, is characterized by myocardial fibrosis, ventricular remodelling and cardiac dysfunction. It has been documented that mitochondrial dysfunction, oxidative stress, inflammatory response, autophagy, apoptosis, diabetic microangiopathy and myocardial fibrosis are implicated in the pathogenesis of diabetic cardiomyopathy. With the development of molecular biology technology, accumulating evidence demonstrates that non‐coding RNAs (ncRNAs) are critically involved in the molecular mechanisms of diabetic cardiomyopathy. In this review, we summarize the pathological roles of three types of ncRNAs (microRNA, long ncRNA and circular RNA) in the progression of diabetic cardiomyopathy, which may provide valuable insights into the pathogenesis of diabetic cardiovascular complications.


| INTRODUC TI ON
Diabetic cardiomyopathy is a type of cardiac dysfunction that develops in the absence of hypertensive heart disease, coronary artery disease and valvular heart disease. 1 It is characterized by myocardial fibrosis, ventricular enlargement and cardiac dysfunction that ultimately leads to heart failure. Emerging evidence implicates that mitochondrial dysfunction, oxidative stress, inflammatory response, autophagy, apoptosis, diabetic microangiopathy and myocardial metabolic abnormalities are involved in the development of diabetic cardiomyopathy. 2 Hyperglycaemia can exert adverse effects on myocardial tissue through various mechanisms, including metabolic disturbance, microvascular impairment and subcellular structure abnormalities.
In recent years, non-coding RNAs (ncRNAs) have important functional implications for human health and disease. 3 There are many types of ncRNAs, 4 and the main classes of functional ncRNAs that are not translated into proteins include microRNA (miRNA), long ncRNA (ln-cRNA) and circular RNA (circRNA). The biogenesis of ncRNAs is complex, and the specific process is shown in Figure 1. It has been reported that ncRNAs participate in the pathogenesis of multiple cardiovascular diseases by both transcriptional and post-transcriptional regulation. [5][6][7] In the present review, we summarize the important roles of miRNA, lncRNA and circRNA in the pathogenesis of diabetic cardiomyopathy.

| MIRNA S
miRNAs are highly conserved and single-stranded ncRNAs that include 20-22 nucleotides. Their primary function is to negatively modulate gene expression through binding to the target mRNA and subsequently inducing its degradation or suppressing the translation. 8 miRNAs can regulate the translation of more than 60% of protein-coding genes. The available evidence indicates that miRNAs can regulate cardiac hypertrophy, 9 myocardial fibrosis, 10 oxidative stress and apoptosis, 11 mitochondrial dysfunction, 12 epigenetic modification, 13 cardiac electrical remodelling 14 and other pathophysiological changes, 15 which are associated with diabetic cardiomyopathy.

| Cardiac hypertrophy
Multiple miRNAs have been reported to modulate cardiac hypertrophy in diabetic cardiomyopathy. Antihypertrophic miRNAs include miR-1, 16 miR-30c, 17 miR-181a, 18 miR-150, 9 miR-133a 19 and miR-373. 20 Prohypertrophic miRNAs include miR-208a, 21 miR-451 22 and miR-195. 23  F I G U R E 1 A, The biogenesis of miRNA and lncRNA. The miRNA is transcribed as primary miRNA (pri-miRNA) by RNA polymerase II (RNAPII). Following processing by the Drosha and DRCG8, precursor miRNA (pre-miRNA) is exported from the nucleus by exportin 5. Then, it undergoes further processing by Dicer and TAR RNA-binding protein (TRBP) to generate mature miRNA loaded into the RNA-induced silencing complex (RISC). The lncRNA is transcribed mostly by RNAPII, and its biogenesis process is similar to miRNA. B, The biogenesis of circRNA. a, e. circRNA by direct back-splicing; b. circular intronic RNA (ciRNA) by back-splicing; c. mRNA by canonical splicing; d. exon-intron circRNA (EIciRNA) by lariat-driven circularization Involvement of miR-1 in cardiomyocyte development and hypertrophic remodelling is indicated by the inverse correlation of MCU expression with muscle-specific miR-1. miR-150 can inhibit cardiomyocyte hypertrophy induced by high glucose through targeting the transcriptional coactivator p300. 9 In addition, miR-208a was found to promote cardiac hypertrophy by inhibiting myostatin and GATA4 expression and upregulating β-myosin heavy chain. 21

| Myocardial fibrosis
Myocardial fibrosis is a typical pathological characteristic of diabetic cardiomyopathy, and it is regulated by miR-133a, 10 miR-15a/b, 37 miR-21, 38 miR-29 39 and miR-200b. 40 Liu et al 38 revealed that miR-21 was upregulated in cardiac fibroblasts exposed to high glucose and could accelerate collagen synthesis through the c-Jun N-terminal kinase and p38 signalling pathways. miR-15a/b were found to be downregulated in the myocardium of diabetic patients and consequently activate fibrotic signalling of transforming growth factor-β receptor-1 and connective tissue growth factor (CTGF). 37

| Oxidative stress
Oxidative stress is critically involved in the pathogenesis of diabetic cardiomyopathy. It has been documented that miR-1, 41

| Other pathophysiological processes
miRNAs can also actively participate in the pathogenesis of cardiac structural damage, 46 mitochondrial dysfunction, 47 inflammatory response, 48,49 angiogenic regulation 50 and myocardial electrical remodelling. 14 Arnold et al 46 reported that miR-29 overexpression in a diabetes model was associated with cardiac structural damage and accompanied by decreased expression of myeloid cell leukaemia 1, a protein that promotes cell survival. In another diabetes model, increased miR-141 expression affected ATP production by decreasing mitochondrial phosphate transport. 47 Reddy et al 48

indicated that disruption of the negative regulatory loop involving miR-200 and
Zeb1 increased inflammatory response in vascular smooth muscle cells under diabetic conditions. In the diabetic heart, miR-146a was associated with elevated inflammatory factor and extracellular matrix protein production and cardiac functional alterations. 49 In addition, miR-193-5p was found to be actively involved in the development of diabetic cardiomyopathy, possibly through negatively regulating its downstream gene IGF2. 50

| LN CRNA S
lncRNAs, a class of transcripts which are longer than 200 nucleotides without protein-coding potential, have been implicated in multiple biological processes, including genomic imprinting, transcriptional regulation, nuclear organization and compartmentalization, RNA splicing and nuclear-cytoplasmic trafficking. [53][54][55][56] In recent years, growing evidence has suggested that lncRNAs can actively participate in the pathogenesis of diverse cardiovascular diseases, including diabetic cardiomyopathy. 57

| Cardiomyocyte apoptosis and autophagy
Some lncRNAs have been identified to be correlated with cardiomyocyte apoptosis and autophagy during the process of diabetic cardiomyopathy. 65 Recently, our research group found that myocardial infarction-associated transcript (MIAT) was upregulated in the diabetic myocardium, while MIAT knockdown could reduce cardiomyocyte apoptosis and improve cardiac dysfunction. 66 We then further investigated the molecular mechanisms involved and found that MIAT acted as a ceRNA to increase DAPK2 expression by sponging miR-22-3p, thus leading to elevated cardiomyocyte apoptosis. 66 Moreover, we generated a diabetic rat model induced by streptozocin and found that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression was increased in the diabetic heart. MALAT1 knockdown was associated with improved cardiac function, partly through the suppression of cardiomyocyte apoptosis. 67 The lncRNA-H19 is a member of conserved imprinted gene family and participates in embryonic development and growth regulation.
In the previous study, we investigated the pathological roles of H19 in the development of diabetic cardiomyopathy. The results indicated that H19 was downregulated in the diabetic myocardium and high glucose treatment contributed to cardiomyocyte apoptosis by modulating H19/ miR-675/VDAC1 pathway. 68 In addition, another study by Zhuo et al 69 revealed that high glucose could downregulate H19 expression and promote autophagy in myocardial cells. H19 overexpression could reduce DIRAS3 expression, increase mTOR phosphorylation and suppress autophagy activation. Thus, H19 is involved in the modulation of autophagy in diabetic cardiomyopathy by epigenetically silencing of DIRAS3.

| Inflammation
Inflammation has a significant involvement in the progression of diabetic cardiomyopathy. 65 Our research group previously found that MALAT1 expression was increased in the diabetic heart, and its knockdown could improve cardiac systolic function and reduce the levels of inflammatory cytokines such as TNF-α, IL-6 and IL-1β in the diabetic myocardium, thus indicating that MALAT1 might be related to the inflammatory response in diabetic cardiomyopathy. 70

| CON CLUS ION
In the present review, we summarize the recent progress in the involvement of ncRNAs in the pathogenesis of diabetic cardiomyopathy. As shown in Table 1

ACK N OWLED G EM ENTS
This study was financially supported by the National Natural Science Foundation of China (81770370) and Scientific Research Program for Young Talents of China National Nuclear Corporation (51001).

CO N FLI C T S O F I NTE R E S T
The authors declare that there are no conflicts of interest.

Wei Zhang and Weiting Xu wrote the manuscript; Yu Feng and Xiang
Zhou revised the manuscript.

DATA ACCE SS I B I LIT Y
I confirm that I have included a citation for available data in my references section.