LncRNA H19 ameliorates myocardial infarction‐induced myocardial injury and maladaptive cardiac remodelling by regulating KDM3A

Abstract

Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide, and novel therapeutic targets still need to be investigated to alleviate myocardial injury and the ensuing maladaptive cardiac remodelling. Accumulating studies have indicated that lncRNA H19 might exert a crucial regulatory effect on cardiovascular disease. In this study, we aimed to explore the biological function and molecular mechanism of H19 in MI. To investigate the biological functions of H19, miRNA‐22‐3p and KDM3A, gain‐ and loss‐of‐function experiments were performed. In addition, bioinformatics analysis, dual‐luciferase reporter assays, RNA immunoprecipitation (RIP) assays, RNA pull‐down assays, quantitative RT‐PCR and Western blot analyses as well as rescue experiments were conducted to reveal an underlying competitive endogenous RNA (ceRNA) mechanism. We found that H19 was significantly down‐regulated after MI. Functionally, enforced H19 expression dramatically reduced infarct size, improved cardiac performance and alleviated cardiac fibrosis by mitigating myocardial apoptosis and decreasing inflammation. However, H19 knockdown resulted in the opposite effects. Bioinformatics analysis and dual‐luciferase assays revealed that, mechanistically, miR‐22‐3p was a direct target of H19, which was also confirmed by RIP and RNA pull‐down assays in primary cardiomyocytes. In addition, bioinformatics analysis and dual‐luciferase reporter assays also demonstrated that miRNA‐22‐3p directly targeted the KDM3A gene. Moreover, subsequent rescue experiments further verified that H19 regulated the expression of KDM3A to ameliorate MI‐induced myocardial injury in a miR‐22‐3p‐dependent manner. The present study revealed the critical role of the lncRNAH19/miR‐22‐3p/KDM3A pathway in MI. These findings suggest that H19 may act as a potential biomarker and therapeutic target for MI.

Piperine protects against pyroptosis in myocardial ischaemia/reperfusion injury by regulating the miR‐383/RP105/AKT signalling pathway

“…Based on the above findings, we further explored the potential molecular mechanisms by which PIP exerted its protective effects against I/R injury and pyroptosis. miRNAs are a group of non‐coding RNAs and could repress target genes via direct bonding to 3′UTR of mRNA 10,27,28 . Previous studies indicated that PIP exerted pharmacological effects via miRNA‐dependent manners 16,17 .…”

“…Recombinant adenoviral vector encoding miR‐383 and its negative control was obtained from GeneChem, Inc 3,27,28 . In brief, the entire coding region of miR‐383 was cloned into shuttle vector GV135 (Shanghai, GeneChem, Inc.).…”

Long non-coding RNA H19 in atherosclerosis: what role?

“…Atherosclerosis is the major cause of coronary artery disease, leading to myocardial ischemia and infarction (Barquera et al 2015 ; de Valk and Marx 1999 ). In addition to the regulation of vascular function, lncRNA-H19 has been suggested to participate in cardiomyocyte injury induced by ischemia/reperfusion (I/R) or infarction (Zhang et al 2020 ; Li et al 2019b ).…”

“…It was found that lncRNA-H19 expression is significantly decreased in the infarcted myocardium of mice, and overexpression of lncRNA-H19 in AMI mice reduces infarct size and improve cardiac function by activating autophagy (Zhou et al 2018 ). Using a rat model of AMI, Zhang et al revealed that lncRNA-H19 sponges miR-22-3p to ameliorate AMI-induced myocardial damage by upregulating lysine (K)-specific demethylase 3A (KDM3A) (Zhang et al 2020 ). It was also reported that lncRNA-H19 protects H9C2 cells against hypoxia-induced injury by sponging miR-139, which targets Sex determining region Y (SRY)-related high-mobility group box 8 (Sox8) (Gong et al 2017 ).…”

Identification of a competing endogenous RNA network associated with prognosis of pancreatic adenocarcinoma

“…The ceRNA hypothesis suggests that lncRNA competitively binds with microRNAs through microRNA response elements (MREs) and inhibits the down-regulation of mRNA translation by miRNAs [12]. Moreover, the role of lncRNA-miRNA-mRNA ceRNA regulatory networks has been revealed in different diseases, such as chronic myeloid leukemia, cardiovascular diseases, diabetic cataract, and myocardial infarction [13][14][15][16], which might impact the prognosis of the diseases. However, on the basis of high-throughput sequencing and large samples, only a few literatures have reported the role of ceRNA in PAAD.…”