LncRNA MALAT1 protects cardiomyocytes from isoproterenol‐induced apoptosis through sponging miR‐558 to enhance ULK1‐mediated protective autophagy

Abstract

Investigating the molecular mechanisms of myocardial infarction (MI) and subsequent heart failure have gained considerable attention worldwide. Long noncoding RNA (lncRNA) metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) has been previously demonstrated to regulate the proliferation and metastasis of several tumors. However, little is known about the effects of MALAT1 in MI and in regulating the cell date after MI. In our study, first, it was shown that the expression levels of MALAT1 were increased in the MI samples compared with normal tissues using quantitative reverse‐transcription polymerase chain reaction. Then, MALAT1 knockdown could significantly decrease the cell viability and increase the apoptotic rates in isoproterenol (ISO)‐treated H9C2 cells. In addition, we screened the possible target and found that miR‐558 is its direct target using dual luciferase reporter assay, indicating that MALAT1 functioned as decoys sponging miR‐558. Transfection of miR‐558 mimic decreased the cell viability and enhanced the apoptosis. Furthermore, we revealed that miR‐558 could downregulate ULK1 expression and suppressed ISO‐induced protective autophagy. Activation of MALAT1/miR‐558/ULK1 pathway protected H9C2 cells from ISO‐induced mitochondria‐dependent apoptosis. Finally, we used MALAT1‐knockout mice to further demonstrated that MALAT1 protected cardiomyocytes from apoptosis and partially improved the cardiac functions upon ISO treatment. In conclusion, we elucidated that lncRNA MALAT1 protected cardiomyocytes from ISO‐induced apoptosis by sponging miR‐558 thus promoting ULK1‐dependent autophagy. Targeting lncRNA MALAT1 might become a potential strategy in protecting cardiomyocytes during MI.

The role of lncRNA MALAT1 in cardiovascular disease

“…Prolonged hypertrophy of cardiomyocytes leads to heart failure . Isoproterenol (ISO) was also found to induce the hypertrophy or mitochondria‐dependent apoptosis of H9C2 cells . MALAT1 protected cardiomyocytes against ISO induced apoptosis and improved the cardiac functions upon via inhibition of miR‐558 .…”

“…Isoproterenol (ISO) was also found to induce the hypertrophy or mitochondria‐dependent apoptosis of H9C2 cells . MALAT1 protected cardiomyocytes against ISO induced apoptosis and improved the cardiac functions upon via inhibition of miR‐558 . Consistently, miR‐558 mimic decreased the cell viability and enhanced the apoptosis via inhibition of threonine UNC‐51‐like kinase, which exert protective effect by inducing autophagy …”

Exosomes Derived From Epigallocatechin Gallate-Treated Cardiomyocytes Attenuated Acute Myocardial Infarction by Modulating MicroRNA-30a

“…Apoptosis and autophagy are two pivotal events of programmed cell death in the pathological mechanisms of AMI injury (Bao et al, 2018). Cardiomyocyte apoptosis and autophagy occur during sustained and severe ischemia, usually involving myocardial pump failure (Guo et al, 2019). Studies have reported that autophagy plays a dual role, an opposite role in heart disease, whereas excessive autophagy resulting from prolonged hypoxia may induce cell death and cardiac dysfunction (Jian et al, 2015).…”

Novel Mechanisms of Exercise-Induced Cardioprotective Factors in Myocardial Infarction

“…miR-21, a miRNA transcribed by RNA polymerase II, is widely expressed in endothelial cells and exerts protective functions after Guo et al, 2019;Huang S. et al, 2019;Sun and Zhang, 2019 DAPK2, death associated protein kinase 2; Drp1, dynamin-related protein-1; KBTBD7, kelch repeat and BTB (POZ) domain containing 7; lncRNA, long non-coding RNA; MI, myocardial infarction; miR, microRNA; MALAT1, metastasis associated lung adenocarcinoma transcript 1; MSC, mesenchymal stem cell; NF-κB, nuclear factor-κB; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TNF-α, tumor necrosis factor-α.…”

“…It was initially reported that genetic deletion or pharmacological inhibition of MALAT1 reduced vascular growth in vivo, suggesting that MALAT1 promoted angiogenesis in ischemic diseases (Michalik et al, 2014). Besides, it has been shown that MALAT1 protects against cardiomyocyte apoptosis after MI by sponging miR-558, thereby inducing Unc-51-like autophagyactivating kinase 1-dependent protective autophagy (Guo et al, 2019). However, a recent study reported that MALAT1 promoted cardiac fibrosis and deteriorated cardiac function post-MI by increasing TGF-β1 activity and inhibiting miR-145 expression (Huang S. et al, 2019).…”