坏死性下垂
Piwi相互作用RNA
DNA甲基化
信使核糖核酸
细胞生物学
甲基化
下调和上调
DNMT1型
生物
分子生物学
化学
癌症研究
基因表达
程序性细胞死亡
核糖核酸
细胞凋亡
生物化学
基因
RNA干扰
作者
Kai Wang,Fuhai Li,Luqian Zhou,Xuemei Zhao,Xiangqian Gao,Cui‐Yun Liu,Xin‐Min Li,Xinzhe Chen,Yan Zhao,Xueli Cheng,Rui Wang,Ruifeng Li,Yu‐Hui Zhang,Fei Gao,Jing Tian,Kun Wang
标识
DOI:10.1002/advs.202304329
摘要
Abstract PIWI‐interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis‐associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)‐mediated 5‐methylcytosine (m 5 C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)‐exposed cardiomyocytes and I/R‐injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m 5 C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA‐mediated m 5 C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP‐DNMT1‐ATF7‐CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.
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