首页|Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3 β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy

Mitochondrial aldehyde dehydrogenase rescues against diabetic cardiomyopathy through GSK3 β-mediated preservation of mitochondrial integrity and Parkin-mediated mitophagy

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Mitochondrial aldehyde dehydrogenase(ALDH2)offers proven cardiovascular benefit although its impact in diabetes remains elusive.This study examined the effect of ALDH2 overexpression(OE)and knockout(KO)on diabetic cardiomyopathy and mechanism involved with a focus on mitochondrial integrity.ALDH2 OE and KO mice were challenged with streptozotocin(STZ,200 mg/kg.i.p.)to establish diabetes.Diabetic patients displayed reduced plasma ALDH2 activity,cardiac remodeling,and diastolic dysfunction.STZ challenge prompted reduced respiratory exchange ratio,dampened fractional shortening,ejection fraction,increased left ventricular(LV)end-systolic and diastolic diameters,cardiac remodeling,cardiomyocyte contractile,and intracellular Ca2 + defects(depressed peak shortening and maximal velocity of shortening/relengthening,prolonged relengthening,dampened intracellular Ca2 + rise and clearance),myocardial ultrastructural injury,oxidative stress,apoptosis,and mitochondrial damage,the effects of which were overtly attenuated and accentuated by ALDH2 OE and KO,respectively.Immunoblotting revealed downregulated mitochondrial proteins PPAR γ coactivator 1 α(PGC-1 α)and UCP-2,Ca2 + regulatory proteins including SERCA and Na+-Ca2 + exchanger,elevated phospholamban,dampened autophagy and mitophagy(LC3B ratio,TOM20,Parkin,FUNDC1,and BNIP3),disrupted phosphorylation of Akt,GSK3 β,and Foxo3a,and elevated PTEN phosphorylation,the effect of which was reversed and worsened by ALDH2 OE and KO,respectively(except FUNDC1 and BNIP3).In vivo and in vitro data revealed that novel ALDH2 activator torezolid/Alda-1 protected against STZ or high glucose-induced cardiac anomalies,the effect was nullified by inhibition of Akt,GSK3 β,Parkin,and mitochondrial coupling.Our data discerned a vital role for ALDH2 in diabetic cardiomyopathy possibly through regulation of Akt,GSK3 β activation,Parkin mitophagy,and mitochondrial function.

ALDH2diabetesmitophagycardiac contractionGSK3 βmitochondrial function

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

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Department of Cardiology,Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital Fudan University,Shanghai 710032,China

National Clinical Research Center for Interventional Medicine,Shanghai 200032,China

Department of Cardiovascular Surgery,Guangdong Provincial Hospital of Chinese Medicine,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510120,Guangdong,China

The Second Clinical College of Guangzhou University of Chinese Medicine,Guangzhou 510405,Guangdong,China

Cardiovascular Department,Shanghai Xuhui Central Hospital,Fudan University,Shanghai 200031,China

Key Laboratory of Resource Biology and Biotechnology in Western China,Ministry of Education,School of Life Sciences and Medicine,Northwest University,Xi'an,China

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,China

Department of Cardiovascular Surgery,Xijing Hospital,Air Force Medical University,710032 China

Department of Cardiology,Affiliated Hospital of Nantong University,Jiangsu 226001,China

School of Pharmacy,Xianning Medical College,Hubei University of Science and Technology,Xianning 437100,China

Xi'an International Medical Center Hospital Affiliated to Northwest University,Xi'an 710077,China

Division of Cardiovascular Sciences,Faculty of Biology,Medicine and Health,The University of Manchester,Manchester,UK

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State Key Laboratory of Dampness Syndrome of Traditional Chinese Medicine jointly established by Guangdong province and the Scientific Research Initiation Project of Guangdong Provincial Hospital of Traditional Chinese MedicineGuangzhou School(College)Joint Sponsorship Project for Fundamental and Applied ResearchProgram of Shanghai Academic/Technology Research Leader

SZ2022KF102021KT170920220102060520XD1420900

2023

10.1093/jmcb/mjad056

分子细胞生物学报(英文版)
中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD
影响因子：0.595
ISSN：1673-520X
年,卷(期)：2023.(9)
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