Department of Physiology, Fourth Military Medical University, Xi'an, China.
J Am Coll Cardiol. 2009 Dec 1;54(23):2187-96. doi: 10.1016/j.jacc.2009.04.100.
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.
Binge drinking may exert cardiac toxicity and interfere with heart function, manifested as impaired ventricular contractility, although the underlying mechanism remains poorly defined.
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).
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.
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.
本研究旨在评估通过系统性过表达线粒体乙醛脱氢酶 2（ALDH2）来促进乙醛（乙醇的主要代谢产物）解毒，对急性乙醇暴露引起的心肌损伤的作用。
狂饮可能会产生心脏毒性并干扰心脏功能，表现为心室收缩力受损，尽管其潜在机制仍未完全明确。
使用鸡β-肌动蛋白启动子产生 ALDH2 转基因小鼠。野生型 FVB（朋友病毒 B）和 ALDH2 小鼠接受乙醇（3 g/kg，腹腔内注射）挑战，24 小时后使用 Langendroff 和心肌细胞边缘检测系统评估心脏功能。Western blot 分析用于评估蛋白磷酸酶 2A 和 2C（PP2A 和 PP2C）、Akt 的磷酸化、AMP 激活的蛋白激酶（AMPK）和转录因子 Foxo3（Thr32 和 Ser413）的磷酸化。
ALDH2 降低了乙醇诱导的心脏乙醛水平升高。急性乙醇挑战恶化了心肌和心肌细胞的收缩功能，表现为最大压力发展速度和下降（+/-dP/dt）、左心室发展压力、细胞缩短和延长再延长时间的降低，这些作用被 ALDH2 缓解。乙醇处理抑制了 Akt 和 AMPK 的磷酸化，与 PP2A 和 PP2C 的上调有关，而 ALDH2 则消除了这种作用。ALDH2 显著减弱了乙醇诱导的 Akt 和 AMPK 刺激的 Foxo3 的 Thr32 和 Ser413 磷酸化的降低。一致地，ALDH2 挽救了乙醇诱导的心肌细胞凋亡、蛋白质损伤和线粒体膜电位去极化。
我们的结果表明，ALDH2 对急性乙醇毒性具有心脏保护作用，可能是通过抑制蛋白磷酸酶，导致 Akt 和 AMPK 的激活增强，随后抑制 Foxo3、凋亡和线粒体功能障碍。
