Current status and strategies of long noncoding RNA research for diabetic cardiomyopathy

Abstract

Long noncoding RNAs (lncRNAs) are endogenous RNA transcripts longer than 200 nucleotides which regulate epigenetically the expression of genes but do not have protein-coding potential. They are emerging as potential key regulators of diabetes mellitus and a variety of cardiovascular diseases. Diabetic cardiomyopathy (DCM) refers to diabetes mellitus-elicited structural and functional abnormalities of the myocardium, beyond that caused by ischemia or hypertension. The purpose of this review was to summarize current status of lncRNA research for DCM and discuss the challenges and possible strategies of lncRNA research for DCM. A systemic search was performed using PubMed and Google Scholar databases. Major conference proceedings of diabetes mellitus and cardiovascular disease occurring between January, 2014 to August, 2018 were also searched to identify unpublished studies that may be potentially eligible. The pathogenesis of DCM involves elevated oxidative stress, myocardial inflammation, apoptosis, and autophagy due to metabolic disturbances. Thousands of lncRNAs are aberrantly regulated in DCM. Manipulating the expression of specific lncRNAs, such as H19, metastasis-associated lung adenocarcinoma transcript 1, and myocardial infarction-associated transcript, with genetic approaches regulates potently oxidative stress, myocardial inflammation, apoptosis, and autophagy and ameliorates DCM in experimental animals. The detail data regarding the regulation and function of individual lncRNAs in DCM are limited. However, lncRNAs have been considered as potential diagnostic and therapeutic targets for DCM. Overexpression of protective lncRNAs and knockdown of detrimental lncRNAs in the heart are crucial for defining the role and function of lncRNAs of interest in DCM, however, they are technically challenging due to the length, short life, and location of lncRNAs. Gene delivery vectors can provide exogenous sources of cardioprotective lncRNAs to ameliorate DCM, and CRISPR-Cas9 genome editing technology may be used to knockdown specific lncRNAs in DCM. In summary, current data indicate that LncRNAs are a vital regulator of DCM and act as the promising diagnostic and therapeutic targets for DCM.

Keywords: Diabetic cardiomyopathy; H19; Long noncoding RNAs; MALAT1; MIAT; MT-LIPCAR; SENCR.

Fig. 1

Pathogenesis of diabetic cardiomyopathy. In diabetes mellitus, repressed glucose oxidation, enhanced fatty acid metabolism, hyperinsulinemia, insulin resistance, and accumulation of advanced glycation end-products lead to oxidative stress, microcirculation impairment, mitochondrial dysfunction, and autonomic neuropathy. These pathogenic factors together result in myocardial inflammation, endothelial dysfunction, necrosis, apoptosis, autophagy, fibrosis, athrosclerosis, and cardiac hypertrophy, impair Ca²⁺ homeostasis, and activate the renin-angiotensin system (RAS). Eventually these pathogenic changes in the myocardium impair the diastolic and systolic function of the heart

Fig. 2

Long noncoding RNAs (lncRNAs) impact the pathophysiological process of diabetic cardiomyopathy. Long noncoding RNAs are regulated in diabetic cardiomyopathy. Changes in the expression of long noncoding RNAs in myocardial tissues influence oxidative stress, myocardial inflammation, cardiomyocyte apoptosis, autophagy, and microvascular impairments. MALAT1: metastasis-associated lung adenocarcinoma transcript 1; MIAT: myocardial infarction-associated transcript; MT-LIPCAR: the mitochondrially encoded long non-coding cardiac associated RNA; SENCR: smooth muscle and endothelial cell-enriched migration/differentiation-associated long noncoding RNA