LncRNA-ZFAS1 Promotes Myocardial Ischemia-Reperfusion Injury Through DNA Methylation-Mediated Notch1 Down-Regulation in Mice

Mengmeng Li; Lei Jiao; Yingchun Shao; Haodong Li; Lihua Sun; Qi Yu; Manyu Gong; Dongping Liu; Yanying Wang; Lina Xuan; Xuewen Yang; Yunmeng Qu; Yaqi Wang; Lintong Jiang; Jingjing Han; Ying Zhang; Yong Zhang

doi:10.1016/j.jacbts.2022.06.004

LncRNA-ZFAS1 Promotes Myocardial Ischemia-Reperfusion Injury Through DNA Methylation-Mediated Notch1 Down-Regulation in Mice

JACC Basic Transl Sci. 2022 Sep 26;7(9):880-895. doi: 10.1016/j.jacbts.2022.06.004. eCollection 2022 Sep.

Authors

Mengmeng Li¹, Lei Jiao¹, Yingchun Shao¹, Haodong Li¹, Lihua Sun¹, Qi Yu¹, Manyu Gong¹, Dongping Liu¹, Yanying Wang¹, Lina Xuan¹, Xuewen Yang¹, Yunmeng Qu¹, Yaqi Wang¹, Lintong Jiang¹, Jingjing Han¹, Ying Zhang¹, Yong Zhang¹

Affiliation

¹ Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, People's Republic of China.

Abstract

The most devastating and catastrophic deterioration of myocardial ischemia-reperfusion injury (MIRI) is cardiomyocyte death. Here we aimed to evaluate the role of lncRNA-ZFAS1 in MIRI and delineate its mechanism of action. The level of lncRNA-ZFAS1 was elevated in MIRI hearts, and artificial knockdown of lncRNA-ZFAS1 in mice improved cardiac function. Notch1 is a potential target of lncRNA-ZFAS1, and lncRNA-ZFAS1 could bind to the promoter region of Notch1 and recruit DNMT3b to induce Notch1 methylation. Nicotinamide mononucleotide could promote the expression of Notch1 by competitively inhibiting the expression of DNMT3b and improving the apoptosis of cardiomyocytes and cardiac function.

Keywords: AAV, adeno-associated virus; DNA methylation; DNMT, DNA methyltransferase; HR, hypoxia/reoxygenation; MI, myocardial infarction; MIRI, myocardial ischemia-reperfusion injury; NICD, Notch intracellular domain; NMCM, neonatal mouse cardiac myocytes; NMN, nicotinamide mononucleotide; Notch1; ROS, reactive oxygen species; TG, transgenic; WT, wild-type; ZFAS1; ZFAS1, zinc finger antisense 1; lncRNA, long noncoding RNA; long noncoding RNA; myocardial ischemia-reperfusion injury; shZFAS1, short hairpin RNA ZFAS1; siZFAS1, small interfering RNA ZFAS1.