Inhibiting Rev-erbα-mediated ferroptosis alleviates susceptibility to myocardial ischemia-reperfusion injury in type 2 diabetes

作者全名："Huang, Qin; Tian, Hao; Tian, Liqun; Zhao, Xiaoshuai; Li, Lu; Zhang, Yuxi; Qiu, Zhen; Lei, Shaoqing; Xia, Zhongyuan"

作者地址："[Huang, Qin; Tian, Hao; Zhao, Xiaoshuai; Li, Lu; Zhang, Yuxi; Qiu, Zhen; Lei, Shaoqing; Xia, Zhongyuan] Wuhan Univ, Renmin Hosp, Dept Anaesthesiol, Wuhan 430060, Hubei, Peoples R China; [Tian, Liqun] Chongqing Med Univ, Affiliated Hosp 1, Dept Anaesthesiol, Chongqing, Peoples R China"

通信作者："Xia, ZY (通讯作者)，Wuhan Univ, Renmin Hosp, Dept Anaesthesiol, Wuhan 430060, Hubei, Peoples R China."

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001101486900001

JCR分区：Q1

影响因子：7.1

年份：2023

卷号：209

期号：　

开始页：135

结束页：150

文献类型：Article; Early Access

关键词：Rev-erb alpha; Ferroptosis; Susceptibility; Myocardial ischemia-reperfusion injury; Type-2 diabetes

摘要："The complex progression of type-2 diabetes (T2DM) may result in increased susceptibility to myocardial ischemia-reperfusion (IR) injury. IR injuries in multiple organs involves ferroptosis. Recently, the clock gene Rev-erb alpha has aroused considerable interest as a novel therapeutic target for metabolic and ischemic heart diseases. Herein, we investigated the roles of Rev-erb alpha and ferroptosis in myocardial IR injury during T2DM and its potential mechanisms. A T2DM model, myocardial IR and a tissue-specific Rev-erb alpha(-/- )mouse in vivo were established, and a high-fat high glucose environment with hypoxia-reoxygenation (HFHG/HR) in H9c2 were also performed. After myocardial IR, glycolipid profiles, creatine kinase-MB, AI, and the expression of Rev-erb alpha and ferroptosis-related proteins were increased in diabetic rats with impaired cardiac function compared to non-diabetic rats, regardless of the time at which IR was induced. The ferroptosis inhibitor ferrostatin-1 decreased AI in diabetic rats given IR and LPO levels in cells treated with HFHG/HR, as well as the expression of Rev-erb alpha and ACSL4. The ferroptosis inducer erastin increased AI and LPO levels and ACSL4 expression. Treatment with the circadian regulator nobiletin and genetically targeting Rev-erb alpha via siRNA or CRISPR/Cas9 technology both protected against severe myocardial injury and decreased Rev-erb alpha and ACSL4 expression, compared to the respective controls. Taken together, these data suggest that ferroptosis is involved in the susceptibility to myocardial IR injury during T2DM, and that targeting Rev-erb alpha could alleviate myocardial IR injury by inhibiting ferroptosis."

基金机构：National Natural Science Foundation of China [:81970722]

基金资助正文："<B>Funding</B> This work was supported by the National Natural Science Foundation of China [grant number:81970722] . The organization s had no role in study design, data collection and analysis, data interpretation, decision to publish or in the preparation of the manuscript."