Upregulation of Hsp27 via further inhibition of histone H2A ubiquitination confers protection against myocardial ischemia/reperfusion injury by promoting glycolysis and enhancing mitochondrial function

被引：6

作者：

Shi, Pilong ^{[1
]}

Wu, Jiawei ^{[1
]}

Li, Minghui ^{[2
]}

Cao, Yonggang ^{[1
]}

Wu, Jiabi ^{[1
]}

Ren, Ping ^{[1
]}

Liu, Kai ^{[1
]}

Zhou, Jiajun ^{[1
]}

Sha, Yuetong ^{[1
]}

Zhang, Qianhui ^{[1
]}

Sun, Hongli ^{[1
]}

机构：

[1] Harbin Med Univ Daqing, Dept Pharmacol, Daqing 163319, Heilongjiang, Peoples R China

[2] Harbin Med Univ Daqing, Dept Pharmaceut, Daqing 163319, Heilongjiang, Peoples R China

来源：

CELL DEATH DISCOVERY | 2023年 / 9卷 / 01期

基金：

中国国家自然科学基金;

关键词：

POLYCOMB PROTEIN RING1B; HEAT-SHOCK PROTEINS; TRANSCRIPTIONAL REGULATION; ROS PRODUCTION; NUCLEOSOME; GENE; UBIQUITYLATION; SUPPRESSES; DYNAMICS;

D O I：

10.1038/s41420-023-01762-x

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Research suggests that ischemic glycolysis improves myocardial tolerance to anoxia and low-flow ischemia. The rate of glycolysis during ischemia reflects the severity of the injury caused by ischemia and subsequent functional recovery following reperfusion. Histone H2AK119 ubiquitination (H2Aub) is a common modification that is primarily associated with gene silencing. Recent studies have demonstrated that H2Aub contributes to the development of cardiovascular diseases. However, the underlying mechanism remains unclear. This study identified Hsp27 (heat shock protein 27) as a H2Aub binding protein and explored its involvement in mediating glycolysis and mitochondrial function. Functional studies revealed that inhibition of PRC1 (polycomb repressive complex 1) decreased H2Aub occupancy and promoted Hsp27 expression through inhibiting ubiquitination. Additionally, it increased glycolysis by activating the NF-kappa B/PFKFB3 signaling pathway during myocardial ischemia. Furthermore, Hsp27 reduced mitochondrial ROS production by chaperoning COQ9, and suppressed ferroptosis during reperfusion. A delivery system was developed based on PCL-PEG-MAL (PPM)-PCM-SH (CWLSEAGPVVTVRALRGTGSW) to deliver PRT4165 (PRT), a potent inhibitor of PRC1, to damaged myocardium, resulting in decreased H2Aub. These findings revealed a novel epigenetic mechanism connecting glycolysis and ferroptosis in protecting the myocardium against ischemia/reperfusion injury.

引用

页数：16