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Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases.
J Mol Cell Cardiol. 2010 Aug; 49(2):322-9.JM

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 (3g/kg, i.p.) challenge and cardiomyocyte contractile function was assessed 24h 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-3beta (GSK-3beta). 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-3beta 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.

Authors+Show Affiliations

Department of Physiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032 China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

20362583

Citation

Ma, Heng, et al. "Aldehyde Dehydrogenase 2 Knockout Accentuates Ethanol-induced Cardiac Depression: Role of Protein Phosphatases." Journal of Molecular and Cellular Cardiology, vol. 49, no. 2, 2010, pp. 322-9.
Ma H, Yu L, Byra EA, et al. Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases. J Mol Cell Cardiol. 2010;49(2):322-9.
Ma, H., Yu, L., Byra, E. A., Hu, N., Kitagawa, K., Nakayama, K. I., Kawamoto, T., & Ren, J. (2010). Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases. Journal of Molecular and Cellular Cardiology, 49(2), 322-9. https://doi.org/10.1016/j.yjmcc.2010.03.017
Ma H, et al. Aldehyde Dehydrogenase 2 Knockout Accentuates Ethanol-induced Cardiac Depression: Role of Protein Phosphatases. J Mol Cell Cardiol. 2010;49(2):322-9. PubMed PMID: 20362583.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases. AU - Ma,Heng, AU - Yu,Lu, AU - Byra,Emily A, AU - Hu,Nan, AU - Kitagawa,Kyoko, AU - Nakayama,Keiichi I, AU - Kawamoto,Toshihiro, AU - Ren,Jun, Y1 - 2010/04/01/ PY - 2010/01/14/received PY - 2010/03/23/revised PY - 2010/03/24/accepted PY - 2010/4/6/entrez PY - 2010/4/7/pubmed PY - 2010/9/10/medline SP - 322 EP - 9 JF - Journal of molecular and cellular cardiology JO - J. Mol. Cell. Cardiol. VL - 49 IS - 2 N2 - 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 (3g/kg, i.p.) challenge and cardiomyocyte contractile function was assessed 24h 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-3beta (GSK-3beta). 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-3beta 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. SN - 1095-8584 UR - https://www.unboundmedicine.com/medline/citation/20362583/Aldehyde_dehydrogenase_2_knockout_accentuates_ethanol_induced_cardiac_depression:_role_of_protein_phosphatases_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(10)00127-6 DB - PRIME DP - Unbound Medicine ER -