期刊
CIRCULATION RESEARCH
卷 130, 期 5, 页码 E3-E17出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.121.318992
关键词
apoptosis; long noncoding RNA; myocardial infarction; reactive oxygen species; reperfusion
资金
- National Natural Science Foundation of China [81872871, 82070283, 82073844]
- HMU Marshal Initiative Funding [HMUMIF-21017]
CIRKIL is a detrimental factor in I/R injury, acting via regulating nuclear translocation of Ku70 and DNA double-strand breaks repair. It may be considered as a novel molecular target for the treatment of cardiac conditions associated with I/R injury.
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 H2O2-treated cardiomyocytes. Overexpression of CIRKIL increased the expression of gamma H(2)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 H2O2 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.
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