CIRKIL Exacerbates Cardiac Ischemia/Reperfusion Injury by Interacting With Ku70. Issue 5 (4th March 2022)

• Record Type: Journal Article
• Authors: Xiao, Hongwen; Zhang, Mingyu; Wu, Hao; Wu, Jiaxu; Hu, Xiaoxi; Pei, Xinyu; Li, Danyang; Zhao, Lu; Hua, Qi; Meng, Bo; Zhang, Xiaowen; Peng, Lili; Cheng, Xiaoling; Li, Zhuoyun; Yang, Wanqi; Zhang, Qi; Zhang, Yang; Lu, Yanjie; Pan, Zhenwei
• Is Part Of: Circulation research. Volume 130:Issue 5(2022)
• Publication Date: 2022-03-04
• Subjects: apoptosis -- long noncoding RNA -- myocardial infarction -- reactive oxygen species -- reperfusion; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.121.318992
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Background: Ku70 participates in several pathological processes through mediating repair of DNA double-strand breaks. Our previous study has identified a highly conserved long noncoding RNA cardiac ischemia reperfusion associated Ku70 interacting lncRNA (CIRKIL) that was upregulated in myocardial infarction. The study aims to investigate whether CIRKIL regulates myocardial ischemia/reperfusion (I/R) through binding to Ku70. Methods: CIRKIL transgenic and knockout mice were subjected to 45-minute ischemia and 24-hour reperfusion to establish myocardial I/R model. RNA pull-down and RNA immunoprecipitation assay were used to detect the interaction between CIRKIL and Ku70. Results: The expression of CIRKIL was increased in I/R myocardium and H2 O2 -treated cardiomyocytes. Overexpression of CIRKIL increased the expression of γH2 A.X, a specific marker of DNA double-strand breaks and aggravated cardiomyocyte apoptosis, whereas knockdown of CIRKIL produced the opposite changes. Transgenic overexpression of CIRKIL aggravated cardiac dysfunction, enlarged infarct area, and worsened cardiomyocyte damage in I/R mice. Knockout of CIRKIL alleviated myocardial I/R injury. Mechanistically, CIRKIL directly bound to Ku70 to subsequently decrease nuclear translocation of Ku70 and impair DNA double-strand breaks repair. Concurrent overexpression of Ku70 mitigated CIRKIL overexpression-induced myocardial I/R injury. Furthermore, knockdown of human CIRKIL significantly suppressed cell damage induced by H2 O2 in adult human ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes. Conclusions: CIRKIL is a detrimental factor in I/R injury acting via regulating nuclear translocation of Ku70 and DNA double-strand breaks repair. Thus, CIRKIL might be considered as a novel molecular target for the treatment of cardiac conditions associated with I/R injury. Abstract : Supplemental Digital Content is available in the text.