Abstract | BACKGROUND: METHODS AND RESULTS: ALDH2 transgenic mice were produced with the chicken beta-actin promoter. Wild-type FVB and ALDH2 mice were placed on a 4% alcohol diet or a control diet for 14 weeks. Myocardial and cardiomyocyte contraction, intracellular Ca(2+) handling, histology ( hematoxylin and eosin, Masson trichrome), protein damage, and apoptosis were determined. Western blot was used to monitor the expression of NADPH oxidase, calcineurin, apoptosis-stimulated kinase (ASK-1), glycogen synthase kinase-3beta (GSK-3beta), GATA4, and cAMP-response element binding ( CREB) protein. ALDH2 reduced the chronic alcohol ingestion-induced elevation in plasma and tissue acetaldehyde levels. Chronic alcohol consumption led to cardiac hypertrophy, reduced fractional shortening, cell shortening, and impaired intracellular Ca(2+) homeostasis, the effect of which was alleviated by ALDH2. In addition, the ALDH2 transgene significantly attenuated chronic alcohol intake-induced myocardial fibrosis, protein carbonyl formation, apoptosis, enhanced NADPH oxidase p47( phox) and calcineurin expression, as well as phosphorylation of ASK-1, GSK-3beta, GATA4, and CREB. CONCLUSIONS: The present results suggest that transgenic overexpression of ALDH2 effectively antagonizes chronic alcohol intake-elicited myocardial hypertrophy and contractile defect through a mechanism that is associated, at least in part, with phosphorylation of ASK-1, GSK-3beta, GATA4, and CREB. These data strongly support the notion that acetaldehyde may be an essential contributor to the chronic development of alcoholic cardiomyopathy.
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Authors | Thomas A Doser, Subat Turdi, D Paul Thomas, Paul N Epstein, Shi-Yan Li, Jun Ren |
Journal | Circulation
(Circulation)
Vol. 119
Issue 14
Pg. 1941-9
(Apr 14 2009)
ISSN: 1524-4539 [Electronic] United States |
PMID | 19332462
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Retracted Publication)
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Chemical References |
- Ethanol
- ALDH2 protein, human
- Aldehyde Dehydrogenase
- Aldehyde Dehydrogenase, Mitochondrial
- Acetaldehyde
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Topics |
- Acetaldehyde
(blood)
- Alcoholism
(complications)
- Aldehyde Dehydrogenase
(genetics)
- Aldehyde Dehydrogenase, Mitochondrial
- Animals
- Cardiomegaly
(prevention & control)
- Cloning, Molecular
- DNA Damage
- Echocardiography
- Ethanol
(blood)
- Gene Expression Regulation, Enzymologic
- Heart
(physiopathology)
- Humans
- Mice
- Mice, Transgenic
- Myocardial Contraction
(genetics)
- Myocardium
(pathology)
- Myocytes, Cardiac
(physiology)
- Plasmids
- Restriction Mapping
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