A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type i diabetes-induced cardiac dysfunction: Role of AMPK-regulated autophagy

被引：96

作者：

Guo, Yuli ^{[1
]}

Yu, Wenjun ^{[1
]}

Sun, Dongdong ^{[1
]}

Wang, Jiaxing ^{[1
]}

Li, Congye ^{[1
]}

Zhang, Rongqing ^{[1
]}

Babcock, Sara A. ^{[2
]}

Li, Yan ^{[1
]}

Liu, Min ^{[1
]}

Ma, Meijuan ^{[1
]}

Shen, Mingzhi ^{[1
]}

Zeng, Chao ^{[1
]}

Li, Na ^{[1
]}

He, Wei ^{[1
]}

Zou, Qian ^{[1
]}

Zhang, Yingmei ^{[1
,2
]}

Wang, Haichang ^{[1
]}

机构：

[1] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiol, Xian 710032, Peoples R China

[2] Univ Wyoming, Coll Hlth Sci, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2015年 / 1852卷 / 02期

关键词：

High glucose; ALDH2; Myocardial dysfunction; Autophagy; AMPK; FOXO3a; INDUCED CARDIOMYOCYTE DYSFUNCTION; ACTIVATED PROTEIN-KINASE; FORKHEAD TRANSCRIPTION FACTOR; CONTRACTILE DYSFUNCTION; MYOCARDIAL DYSFUNCTION; THERAPEUTIC TARGET; OXIDATIVE STRESS; SKELETAL-MUSCLE; HEART; OVEREXPRESSION;

D O I：

10.1016/j.bbadis.2014.05.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Mitochondrial aldehyde dehydrogenase (ALDH2) is known to offer myocardial protection against stress conditions including ischemia-reperfusion injury, alcoholism and diabetes mellitus although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on diabetes-induced myocardial injury with a focus on autophagy. Wild-type FVB and ALDH2 transgenic mice were challenged with streptozotozin (STZ, 200 mg/kg, i.p.) for 3 months to induce experimental diabetic cardiomyopathy. Diabetes triggered cardiac remodeling and contractile dysfunction as evidenced by cardiac hypertrophy, decreased cell shortening and prolonged relengthening duration, the effects of which were mitigated by ALDH2. Lectin staining displayed that diabetes promoted cardiac hypertrophy, the effect of which was alleviated by ALDH2. Western blot analysis revealed dampened autophagy protein markers including LOB ratio and Atg7 along with upregulated p62 following experimental diabetes, the effect of which was reconciled by ALDH2. Phosphorylation level of AMPK was decreased and its downstream signaling molecule FOXO3a was upregulated in both diabetic cardiac tissue and in H9C2 cells with high glucose exposure. All these effect were partly abolished by ALDH2 overexpression and ALDH2 agonist Alda1. High glucose challenge dampened autophagy in H9C2 cells as evidenced by enhanced p62 levels and decreased levels of Atg7 and LOB, the effect of which was alleviated by the ALDH2 activator Alda-1. High glucose-induced cell death and apoptosis were reversed by Alda-1. The autophagy inhibitor 3-MA and the AMPK inhibitor compound C mitigated Aids-l-offered beneficial effect whereas the autophagy inducer rapamycin mimicked or exacerbated high glucose-induced cell injury. Moreover, compound C nullified Alda-1-induced protection against STZ-induced changes in autophagy and function. Our results suggested that ALDH2 protects against diabetes-induced myocardial dysfunction possibly through an AMPK -dependent regulation of autophagy. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases. (C) 2014 Elsevier B.V. All rights reserved.

引用

页码：319 / 331

页数：13

共 21 条

[21] Role of PI3K/Akt in Insulin-Mediated Regulation of Cu Transporter ATP7A Function Required for Full Activation of Extracellular SOD in Vasculature: Novel Protective Mechanism for Endothelial Dysfunction in Type I Diabetes
Varadarajan, Sudhahar
Urao, Norifumi
McKinney, Ronald D.
Okur, Nazir
O'Bryan, John P.
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CIRCULATION, 2011, 124 (21)

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