Guo Yuli, Yu Wenjun, Sun Dongdong, Wang Jiaxing, Li Congye, Zhang Rongqing, Babcock Sara A, Li Yan, Liu Min, Ma Meijuan, Shen Mingzhi, Zeng Chao, Li Na, He Wei, Zou Qian, Zhang Yingmei, Wang Haichang
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071 USA.
Biochim Biophys Acta. 2015 Feb;1852(2):319-31. doi: 10.1016/j.bbadis.2014.05.017. Epub 2014 May 27.
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, 200mg/kg, i.p.) for 3months 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 LC3B 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 LC3B, 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 Alda-1-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.
线粒体乙醛脱氢酶（ALDH2）已知可在包括缺血再灌注损伤、酒精中毒和糖尿病等应激条件下为心肌提供保护，尽管其确切机制尚不清楚。本研究旨在评估ALDH2对糖尿病诱导的心肌损伤的影响，重点关注自噬。野生型FVB和ALDH2转基因小鼠腹腔注射链脲佐菌素（STZ，200mg/kg），持续3个月以诱导实验性糖尿病性心肌病。糖尿病引发心脏重塑和收缩功能障碍，表现为心脏肥大、细胞缩短减少和再延长持续时间延长，而ALDH2可减轻这些影响。凝集素染色显示糖尿病促进心脏肥大，而ALDH2可减轻这种影响。蛋白质印迹分析显示，实验性糖尿病后自噬蛋白标志物包括LC3B比率和Atg7减少，同时p62上调，而ALDH2可使这些影响恢复正常。糖尿病心脏组织和高糖暴露的H9C2细胞中，AMPK的磷酸化水平降低，其下游信号分子FOXO3a上调。ALDH2过表达和ALDH2激动剂Alda1可部分消除所有这些影响。高糖刺激可抑制H9C2细胞中的自噬，表现为p62水平升高以及Atg7和LC3B水平降低，而ALDH2激活剂Alda-1可减轻这种影响。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可减轻Alda-1提供的有益作用，而自噬诱导剂雷帕霉素模拟或加剧高糖诱导的细胞损伤。此外，化合物C消除了Alda-1诱导的对STZ诱导的自噬和功能变化的保护作用。我们的结果表明，ALDH2可能通过AMPK依赖的自噬调节来保护心脏免受糖尿病诱导的功能障碍。本文是名为：心脏代谢疾病中的自噬和蛋白质质量控制的特刊的一部分。
