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Involvement of AMPK in alcohol dehydrogenase accentuated myocardial dysfunction following acute ethanol challenge in mice
- Source :
- PLoS ONE, PLoS ONE, Vol 5, Iss 6, p e11268 (2010)
- Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- medicine.medical_specialty
Transgene
medicine.medical_treatment
Cardiovascular Disorders
Blotting, Western
lcsh:Medicine
Mice, Transgenic
Fluorescence
03 medical and health sciences
Mice
0302 clinical medicine
Adenosine Triphosphate
Internal medicine
medicine
Animals
Insulin
Phosphorylation
lcsh:Science
Chromatography, High Pressure Liquid
030304 developmental biology
Alcohol dehydrogenase
0303 health sciences
Multidisciplinary
biology
Ethanol
Kinase
Chemistry
lcsh:R
Adenylate Kinase
Alcohol Dehydrogenase
AMPK
Myocardial Contraction
Adenosine Monophosphate
Insulin receptor
Endocrinology
13. Climate action
030220 oncology & carcinogenesis
biology.protein
Physiology/Cell Signaling
lcsh:Q
Cardiovascular Disorders/Myopathies
Homeostasis
GLUT4
Research Article
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 5
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- PloS one
- Accession number :
- edsair.doi.dedup.....2f7b7f5fef579bb2734bdf19d415a5d9