Dihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS  

作　　者：Xunxun Wu Lian Liu Qiuling Zheng Hui Ye Hua Yang Haiping Hao Ping Li 

机构地区：[1]State Key Laboratory of Natural Medicines,Department of Pharmacognosy,School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 210009,China [2]College of Pharmacy,China Pharmaceutical University,Nanjing 210009,China [3]State Key Laboratory of Natural Medicines,Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第1期113-127,共15页药学学报（英文版）

基　　金：supported by the National Key R&D Program of China(2019YFC1711000);the National Natural Science Foundation of China(No.81421005);the“111”Project(B16046)from the Ministry of Education of China and the State Administration of Foreign Experts Affairs of China。

摘　　要：Ischemic preconditioning(IPC)is a potential intervention known to protect the heart against ischemia/reperfusion injury,but its role in the no-reflow phenomenon that follows reperfusion is unclear.Dihydrotanshinone I(DT)is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC.Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation(OGD),but the protection was prevented by a ROS scavenger.In addition,DT administration protected the heart against isoprenaline challenge.Mechanistically,PKM2 reacted to transient ROS via oxidization at Cys423/Cys424,leading to glutathionylation and nuclear translocation in dimer form.In the nucleus,PKM2 served as a co-factor to promote HIF-1a-dependent gene induction,contributing to adaptive responses.In mice subjected to permanent coronary ligation,cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection,which was rescued by overexpression of wild-type Pkm2,rather than Cys423/424-mutated Pkm2.In conclusion,PKM2 is sensitive to oxidation,and subsequent glutathionylation promotes its nuclear translocation.Although IPC has been viewed as a protective means against reperfusion injury,our study reveals its potential role in protection of the heart from no-reflow ischemia.

关 键 词：Dihydrotanshinone I Ischemic preconditioning PKM2 GLUTATHIONYLATION Myocardial ischemia ROS Oxidation modification Nuclear translocation 

分 类 号：R285.5[医药卫生—中药学]