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mellitus and cardiovascular disease occurring between January, 2014 to August, 2018 were also searched to identify unpublished studies that may be potentially eligible.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.

Long Noncoding RNA SOX2-OT Exacerbates Hypoxia-Induced Cardiomyocytes Injury by Regulating miR-27a-3p/TGFβR1 Axis

“…e long noncoding RNAs (lncRNAs) belonged to a category transcript with no less than 200 nucleotides in length and without protein-coding capacity [9,10]. LncRNAs were proved to take part in the regulation of several biological processes such as cell proliferation, apoptosis, migration, and invasion in a variety of diseases or tumors [11,12]. Long noncoding RNA HOTAIR was reported to accelerate the proliferation, migration, and invasion of head and neck squamous cell carcinoma (HNSCC) cells by sponging microRNA-206 and targeting STC2 [13].…”

MicroRNAs play an essential role in autophagy regulation in various disease phenotypes

“…H19 is a 2.3‐kb lncRNA which is transcribed from insulin‐like growth factor‐II genomic imprinted cluster located on human chromosome 11p15.5; its expression is high in embryonic organs and greatly reduced or absent in most adult tissues. Overexpression of H19 in myocardial tissues caused decreases in inflammation, apoptosis, autophagy, and oxidative stress, leading to the amelioration of diabetic cardiomyopathy . MEG3 is believed to be a tumor‐suppressive lncRNA and correlated negatively with poor prognosis in lung cancer.…”

“…Overexpression of H19 in myocardial tissues caused decreases in inflammation, apoptosis, autophagy, and oxidative stress, leading to the amelioration of diabetic cardiomyopathy. 36 MEG3 is believed to be a tumorsuppressive lncRNA and correlated negatively with poor prognosis in lung cancer. In vitro experiment showed that upregulation of MEG3 increased the sensitivity of A549 cells to cisplatin by activation of the WNT/β-catenin signaling pathway, whereas downregulation of MEG3 caused the opposite effect.…”

Tcf3‐activated lncRNA Gas5 regulates newborn mouse cardiomyocyte apoptosis in diabetic cardiomyopathy

“…21 And the inner mechanism of diabetic cardiomyopathy has been reported before, which has proved that lncRNAs can play the modulating function in diabetic cardiomyopathy. 22,23 For example, KCNQ1OT1 can modulate the cell apoptosis of diabetic cardiomyopathy. 23 lncRNA H19 reduces autophagy in diabetic cardiomyopathy by downregulating the expression of DIRAS3.…”