A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type i diabetes-induced cardiac dysfunction: Role of AMPK-regulated autophagy
A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type i diabetes-induced cardiac dysfunction: Role of AMPK-regulated autophagy
复制标题
线粒体乙醛脱氢酶 (ALDH2) 在 I 型糖尿病引起的心功能障碍中的新型保护机制：AMPK 调节的自噬的作用
DOI：
10.1016/j.bbadis.2014.05.017
复制
发表时间：
2015-02-01
影响因子：
6.2
通讯作者：
Wang, Haichang
中科院分区：
文献类型：
--
作者：
Guo, Yuli;Yu, Wenjun;Wang, Haichang
已知线粒体乙醛脱氢酶(ALDH2)对包括缺血再灌注损伤、酒精中毒和糖尿病在内的应激条件下的心肌具有保护作用，尽管其确切机制尚不清楚。这项研究旨在评估ALDH2对糖尿病所致心肌损伤的影响，重点是自噬。用链脲佐菌素(STZ，200 mg/kg)攻击野生型FVB和ALDH2转基因小鼠。连续3个月诱导实验性糖尿病心肌病。糖尿病引起心脏重构和收缩功能障碍，表现为心肌肥大、细胞缩短和再延长时间延长，ALDH2减轻了这一影响。凝集素染色显示糖尿病促进心肌肥厚，ALDH2可减轻糖尿病心肌肥厚的作用。Western印迹分析显示，实验性糖尿病后自噬蛋白标记物LOB比率和ATG7受到抑制，而p62表达上调，其影响被ALDH2所抵消。在糖尿病心肌组织和高糖暴露的H9C2细胞中，AMPK的磷酸化水平降低，其下游信号分子FOXO3a上调。这些作用可被ALDH2的过度表达和ALDH2激动剂Alda1部分消除。高糖刺激抑制了H9C2细胞的自噬作用，表现为p62水平升高，ATG7和LOB水平下降，其影响可被ALDH2激活剂ALDA-1缓解。ALDA-1可逆转高糖诱导的细胞死亡和凋亡。自噬抑制剂3-MA和AMPK抑制剂化合物C减轻艾滋病-L-提供了有益的作用，而自噬诱导剂雷帕霉素模拟或加剧了高糖诱导的细胞损伤。此外，化合物C取消了ALDA-1对STZ诱导的自噬和功能改变的保护作用。我们的结果表明，ALDH2可能通过AMPK依赖的自噬调节来保护糖尿病引起的心肌功能障碍。本文是题为：心脏代谢性疾病中的自噬和蛋白质质量控制的特刊的一部分。(C)2014爱思唯尔B.V.保留所有权利。
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.