Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: Role of protein phosphatases

Heng Ma, Lu Yu, Emily A. Byra, Nan Hu, Kyoko Kitagawa, Keiichi I. Nakayama, Toshihiro Kawamoto, Jun Ren

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Alcohol consumption leads to myocardial contractile dysfunction possibly due to the toxicity of ethanol and its major metabolite acetaldehyde. This study was designed to examine the influence of mitochondrial aldehyde dehydrogenase-2 (ALDH2) knockout (KO) on acute ethanol exposure-induced cardiomyocyte dysfunction. Wild-type (WT) and ALDH2 KO mice were subjected to acute ethanol (3. g/kg, i.p.) challenge and cardiomyocyte contractile function was assessed 24. h later using an IonOptix edge detection system. Western blot analysis was performed to evaluate ALDH2, protein phosphatase 2A (PP2A), phosphorylation of Akt, and glycogen synthase kinase-3β (GSK-3β). ALDH2 KO accentuated ethanol-induced elevation in cardiac acetaldehyde levels. Ethanol exposure depressed cardiomyocyte contractile function including decreased cell shortening amplitude and maximal velocity of shortening/relengthening as well as prolonged relengthening duration and a greater decline in peak shortening in response to increasing stimulus frequency, the effect of which was significantly exaggerated by ALDH2 KO. ALDH2 KO also unmasked an ethanol-induced prolongation of shortening duration. In addition, short-term in vitro incubation of ethanol-induced cardiomyocyte mechanical defects was exacerbated by the ALDH inhibitor cyanamide. Ethanol treatment dampened phosphorylation of Akt and GSK-3β associated with upregulated PP2A, which was accentuated by ALDH2 KO. ALDH2 KO aggravated ethanol-induced decrease in mitochondrial membrane potential. These results suggested that ALDH2 deficiency led to worsened ethanol-induced cardiomyocyte function, possibly due to upregulated expression of protein phosphatase, depressed Akt activation, and subsequently impaired mitochondrial function. These findings depict a critical role of ALDH2 in the pathogenesis of alcoholic cardiomyopathy.

Original languageEnglish
Pages (from-to)322-329
Number of pages8
JournalJournal of Molecular and Cellular Cardiology
Volume49
Issue number2
DOIs
Publication statusPublished - Aug 1 2010

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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