1. Involvement of AMPK in alcohol dehydrogenase accentuated myocardial dysfunction following acute ethanol challenge in mice
- Author
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Rui Guo, Glenda I. Scott, and Jun Ren
- 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 - 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.
- Published
- 2010