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PRE-CLINICAL RESEARCH

Aldehyde Dehydrogenase 2 Ameliorates Acute Cardiac Toxicity of Ethanol

Role of Protein Phosphatase and Forkhead Transcription Factor

Heng Ma, MD, PhD^_*,, Ji Li, PhD, Feng Gao, MD, PhD^_*, and Jun Ren, MD, PhD^_*,,,_*

^_* Department of Physiology, Fourth Military Medical University, Xi'an, China
Xijing Hospital, Fourth Military Medical University, Xi'an, China
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, Wyoming

Manuscript received October 28, 2008; revised manuscript received March 10, 2009, accepted April 2, 2009.

^_* Reprint requests and correspondence: Dr. Jun Ren, University of Wyoming College of Health Sciences, 1000 East University Avenue, Laramie, Wyoming 82071 (Email: jren{at}uwyo.edu).

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.

Key Words: ethanol • ALDH2 • myocardial dysfunction • Akt • AMPK • Foxo3 • protein phosphatase

Abbreviations and Acronyms   ±dL/dt = maximal velocity of shortening/relengthening   ±dP/dt = maximal velocity of pressure development and decline   ADH = alcohol dehydrogenase   ALDH = aldehyde dehydrogenase   AMPK = AMP-activated protein kinase   LVDP = left ventricular developed pressure   PS = peak shortening   SR = sarcoplasmic reticulum   TPS = time-to-90% peak shortening   TR90 = time-to-90% relengthening   m = mitochondrial membrane potential

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