Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy  

作　　者：Yingmei Zhang Rongjun Zou Miyesaier Abudureyimu Qiong Liu Jipeng Ma Haixia Xu Wei Yu Jian Yang Jianguo Jia Sanli Qian Haichang Wang Yang Yang Xin Wang Xiaoping Fan Jun Ren 

机构地区：[1]Department of Cardiology,Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital Fudan University,Shanghai 710032,China [2]National Clinical Research Center for Interventional Medicine,Shanghai 200032,China [3]Department of Cardiovascular Surgery,Guangdong Provincial Hospital of Chinese Medicine,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510120,China [4]The Second Clinical College of Guangzhou University of Chinese Medicine,Guangzhou 510405,China [5]Cardiovascular Department,Shanghai Xuhui Central Hospital,Fudan University,Shanghai 200031,China [6]Key Laboratory of Resource Biology and Biotechnology in Western China,Ministry of Education,School of Life Sciences and Medicine,Northwest University,Xi’an 710069,China [7]Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases,Xi’an No.3 Hospital,The Affiliated Hospital of Northwest University,School of Life Sciences and Medicine,Northwest University,Xi’an 710069,China [8]Department of Cardiovascular Surgery,Xijing Hospital,Air Force Medical University,Xi’an 710032,China [9]Department of Cardiology,Affiliated Hospital of Nantong University,Nantong 226001,China [10]School of Pharmacy,Xianning Medical College,Hubei University of Science and Technology,Xianning 437100,China [11]Xi’an International Medical Center Hospital Affiliated to Northwest University,Xi’an 710077,China [12]Division of Cardiovascular Sciences,Faculty of Biology,Medicine and Health,The University of Manchester,Manchester M139GB,UK

出　　处：《Journal of Molecular Cell Biology》2023年第9期25-39,共15页分子细胞生物学报（英文版）

基　　金：supported in part by the State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine jointly established by Guangdong Province and the Ministry(SZ2022KF10);Scientific Research Initiation Project of Guangdong Provincial Hospital of Traditional Chinese Medicine(2021KT1709);Guangzhou School(College)Joint Sponsorship Project for Fundamental and Applied Research(202201020605);Program of Shanghai Academic/Technology Research Leader(20XD1420900).

摘　　要：Mitochondrial aldehyde dehydrogenase(ALDH2)offers proven cardiovascular benefit,although its impact on diabetes remains elusive.This study examined the effects of ALDH2 overexpression and knockout on diabetic cardiomyopathy and the mechanism involved with a focus on mitochondrial integrity.Mice challenged with streptozotocin(STZ,200 mg/kg,via intraperitoneal injection)exhibited pathological alterations,including reduced respiratory exchange ratio,dampened fractional shortening and ejection fraction,increased left ventricular end-systolic and diastolic diameters,cardiac remodeling,cardiomyocyte contractile anomalies,intracellular Ca2+defects,myocardial ultrastructural injury,oxidative stress,apoptosis,and mitochondrial damage,which were overtly attenuated or accentuated by ALDH2 overexpression or knockout,respectively.Diabetic patients also exhibited reduced plasma ALDH2 activity,cardiac remodeling,and diastolic dysfunction.In addition,STZ challenge altered expression levels of mitochondrial proteins(PGC-1αand UCP2)and Ca2+regulatory proteins(SERCA,Na+–Ca2+exchanger,and phospholamban),dampened autophagy and mitophagy(LC3B ratio,TOM20,Parkin,FUNDC1,and BNIP3),disrupted phosphorylation of Akt,GSK3β,and Foxo3a,and elevated PTEN phosphorylation,most of which were reversed or worsened by ALDH2 overexpression or knockout,respectively.Furthermore,the novel ALDH2 activator torezolid,as well as the classical ALDH2 activator Alda-1,protected against STZ-or high glucose-induced in vivo or in vitro cardiac anomalies,which was nullified by inhibition of Akt,GSK3β,Parkin,or mitochondrial coupling.Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt and GSK3βactivation,Parkin mitophagy,and mitochondrial function.

关 键 词：ALDH2 diabetes MITOPHAGY cardiac contraction GSK3Β mitochondrial function 

分 类 号：R542.2[医药卫生—心血管疾病]