Long non-coding RNA MIR4435-2HG/microRNA-125a-5p axis is involved in myocardial ischemic injuries. Issue 4 (1st April 2022) - Wang, Xiuling
ABSTRACT: This study aimed to investigate whether and how long non-coding RNA (lncRNA) MIR4435-2 host gene (MIR4435-2HG) involved in acute myocardial ischemia/reperfusion (I/R). Blood samples were collected from acute myocardial infarction (AMI) patients to detect MIR4435-2HG expression. In vivo myocardial I/R mice model and in vitro H2 O2 -induced oxidative stress model were established. Echocardiography, TUNEL assay and lactate dehydrogenase (LDH) detection were performed to assess heart infarction and myocardium apoptosis. Relationship among microRNA-125a-5p (miR-125a-5p), MIR4435-2HG and Mitochondrial fission protein 1 (MTFP1) was predicted by Targetscan and verified by luciferase reporter assay. MIR4435-2HG was notably upregulated in AMI patients, myocardial I/R mice and H2 O2 -treated cells. Knockdown of MIR4435-2HG notably alleviated infraction volume, ejection fraction (EF) and fractional shortening (FS) levels, cell apoptosis portion and pro-apoptotic cleaved-caspase-3 and Cyt c expression caused by myocardial I/R and oxidative stress, as well as improved cardiomyocytes viability. Transfection with miR-125a-5p alleviated MIR4435-2HG-caused cardiomyocytes apoptosis during oxidative stress. MiR-125a-5p overexpression decreased luciferase activity of the wild-type MIR4435-2HG compared with the mutated MIR4435-2HG. The expression levels of MTFP1 were elevated in myocardium from MI mice model and H2 O2 -treated AC16 cardiomyocytes. In addition, miR-125a-5p overexpression inhibited MTFP1 expression, and could stimulate the wild-type MTFP1 promoter luciferase activity but not the mutated one. Our findings revealed the role of MIR4435-2HG in MI-induced myocardium injury and cardiomyocytes apoptosis, disclosed a novel MIR4435-2HG/miR-125a-5p regulatory axis during myocardial I/R, and thus identified a potential target for the therapy of myocardial IR injury. Graphical abstract: uf0001