Aldehyde Dehydrogenase 2 Ameliorates Acute Cardiac Toxicity of Ethanol Role of Protein Phosphatase and Forkhead Transcription Factor
Aldehyde Dehydrogenase 2 Ameliorates Acute Cardiac Toxicity of Ethanol Role of Protein Phosphatase and Forkhead Transcription Factor
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DOI：
10.1016/j.jacc.2009.04.100
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发表时间：
2009-12-01
影响因子：
24
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Ma, Heng;Li, Ji;Ren, Jun
目的探讨乙醇的主要代谢产物乙醛在急性酒精暴露所致心肌损伤中的促进解毒作用。大量饮酒可对心脏产生毒性作用，并干扰心脏功能，表现为心肌收缩功能受损，但其机制尚不清楚。野生型FVB(Friend B病毒)和ALDH2小鼠以3g/kg乙醇(3g/kg，腹腔注射)攻击，24 h后用Langendroff和心肌细胞边缘检测系统评价心功能。Western印迹分析蛋白磷酸酶2A和2C(PP2A和PP2C)、Akt的磷酸化、AMP活化的蛋白激酶(AMPK)和转录因子Foxo3(Thr32和Ser413)。急性乙醇刺激使心肌和心肌细胞收缩功能恶化，表现为最大压力发展和下降速度(+/-dp/dt)降低，左心室发展压降低，细胞缩短，再长时间延长，这种作用可被ALDH2缓解。乙醇处理抑制了Akt和AMPK的磷酸化，同时上调了PP2A和PP2C，这一作用被ALDH2取消。ALDH2显著减弱乙醇诱导的Akt和AMPK诱导的Foxo3在Thr32和Ser413的磷酸化水平的降低。结论ALDH2对急性乙醇中毒具有心脏保护作用，其机制可能是通过抑制蛋白磷酸酶，增强Akt和AMPK活性，进而抑制Foxo3、细胞凋亡和线粒体功能障碍。(J Am Coll心脏ol 2009；54：2187-96)(C)美国心脏病学会基金会2009
Objectives This study was designed to evaluate the role of facilitated detoxification of acetaldehyde, the main metabolic product of ethanol, through systemic overexpression of mitochondrial aldehyde dehydrogenase-2 (ALDH2) on acute ethanol exposure-induced myocardial damage.Background Binge drinking may exert cardiac toxicity and interfere with heart function, manifested as impaired ventricular contractility, although the underlying mechanism remains poorly defined.Methods ALDH2 transgenic mice were produced using the chicken beta-actin promoter. Wild-type FVB (friend virus B) and ALDH2 mice were challenged with ethanol (3 g/kg, intraperitoneally), and cardiac function was assessed 24 h later using the Langendroff and cardiomyocyte edge-detection systems. Western blot analysis was used to evaluate protein phosphatase 2A and 2C (PP2A and PP2C), phosphorylation of Akt, AMP-activated protein kinase (AMPK), and the transcription factors Foxo3 (Thr32 and Ser413).Results ALDH2 reduced ethanol-induced elevation in cardiac acetaldehyde levels. Acute ethanol challenge deteriorated myocardial and cardiomyocyte contractile function evidenced by reduction in maximal velocity of pressure development and decline (+/-dP/dt), left ventricular developed pressure, cell shortening, and prolonged relengthening duration, the effects of which were alleviated by ALDH2. Ethanol treatment dampened phosphorylation of Akt and AMPK associated with up-regulated PP2A and PP2C, which was abrogated by ALDH2. ALDH2 significantly attenuated ethanol-induced decrease in Akt- and AMPK-stimulated phosphorylation of Foxo3 at Thr32 and Ser413, respectively. Consistently, ALDH2 rescued ethanol-induced myocardial apoptosis, protein damage, and mitochondrial membrane potential depolarization.Conclusions Our results suggest that ALDH2 is cardioprotective against acute ethanol toxicity, possibly through inhibition of protein phosphatases, leading to enhanced Akt and AMPK activation, and subsequently, inhibition of Foxo3, apoptosis, and mitochondrial dysfunction. (J Am Coll Cardiol 2009; 54: 2187-96) (C) 2009 by the American College of Cardiology Foundation