Document Detail

Involvement of AMPK in alcohol dehydrogenase accentuated myocardial dysfunction following acute ethanol challenge in mice.
MedLine Citation:
PMID:  20585647     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: Binge alcohol drinking often triggers myocardial contractile dysfunction although the underlying mechanism is not fully clear. This study was designed to examine the impact of cardiac-specific overexpression of alcohol dehydrogenase (ADH) on ethanol-induced change in cardiac contractile function, intracellular Ca(2+) homeostasis, insulin and AMP-dependent kinase (AMPK) signaling.
METHODS: ADH transgenic and wild-type FVB mice were acutely challenged with ethanol (3 g/kg/d, i.p.) for 3 days. Oral glucose tolerance test, cardiac AMP/ATP levels, cardiac contractile function, intracellular Ca(2+) handling and AMPK signaling (including ACC and LKB1) were examined.
RESULTS: Ethanol exposure led to glucose intolerance, elevated plasma insulin, compromised cardiac contractile and intracellular Ca(2+) properties, downregulated protein phosphatase PP2A subunit and PPAR-gamma, as well as phosphorylation of AMPK, ACC and LKB1, all of which except plasma insulin were overtly accentuated by ADH transgene. Interestingly, myocardium from ethanol-treated FVB mice displayed enhanced expression of PP2Calpha and PGC-1alpha, decreased insulin receptor expression as well as unchanged expression of Glut4, the response of which was unaffected by ADH. Cardiac AMP-to-ATP ratio was significantly enhanced by ethanol exposure with a more pronounced increase in ADH mice. In addition, the AMPK inhibitor compound C (10 microM) abrogated acute ethanol exposure-elicited cardiomyocyte mechanical dysfunction.
CONCLUSIONS: In summary, these data suggest that the ADH transgene exacerbated acute ethanol toxicity-induced myocardial contractile dysfunction, intracellular Ca(2+) mishandling and glucose intolerance, indicating a role of ADH in acute ethanol toxicity-induced cardiac dysfunction possibly related to altered cellular fuel AMPK signaling cascade.
Rui Guo; Glenda I Scott; Jun Ren
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-06-23
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-06-29     Completed Date:  2011-01-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e11268     Citation Subset:  IM    
Center for Cardiovascular Research and Alternative Medicine, College of Health Sciences, University of Wyoming, Laramie, Wyoming, United States of America.
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MeSH Terms
Adenosine Monophosphate / metabolism
Adenosine Triphosphate / metabolism
Adenylate Kinase / metabolism*
Alcohol Dehydrogenase / genetics,  metabolism*
Blotting, Western
Chromatography, High Pressure Liquid
Ethanol / administration & dosage*,  toxicity
Insulin / blood
Mice, Transgenic
Myocardial Contraction / drug effects*
Grant Support
Reg. No./Substance:
11061-68-0/Insulin; 56-65-5/Adenosine Triphosphate; 61-19-8/Adenosine Monophosphate; 64-17-5/Ethanol; EC Dehydrogenase; EC Kinase

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