Overexpression of alcohol dehydrogenase exacerbates ethanol-induced contractile defect in cardiac myocytes.
Alcoholic cardiomyopathy is characterized by impaired ventricular function although its toxic mechanism is unclear. This study examined the impact of cardiac overexpression of alcohol dehydrogenase (ADH), which oxidizes ethanol into acetaldehyde (ACA), on ethanol-induced cardiac contractile defect. Mechanical and intracellular Ca(2+) properties were evaluated in ventricular myocytes from ADH transgenic and wild-type (FVB) mice. ACA production was assessed by gas chromatography. ADH myocytes exhibited similar mechanical properties but a higher efficiency to convert ACA compared with FVB myocytes. Acute exposure to ethanol depressed cell shortening and intracellular Ca(2+) in the FVB group with maximal inhibitions of 23.3% and 23.4%, respectively. Strikingly, the ethanol-induced depression on cell shortening and intracellular Ca(2+) was significantly augmented in the ADH group, with maximal inhibitions of 43.7% and 40.6%, respectively. Pretreatment with the ADH inhibitor 4-methylpyrazole (4-MP) or the aldehyde dehydrogenase inhibitor cyanamide prevented or augmented the ethanol-induced inhibition, respectively, in the ADH but not the FVB group. The ADH transgene also substantiated the ethanol-induced inhibition of maximal velocity of shortening/relengthening and unmasked an ethanol-induced prolongation of the duration of shortening/relengthening, which was abolished by 4-MP. These data suggest that elevated cardiac ACA exposure due to enhanced ADH expression may play an important role in the development of alcoholic cardiomyopathy.
Duan
Jinhong
J
Department of Pharmacology, Physiology, and Therapeutics, Grand Forks, North Dakota 58203, USA.
McFadden
Grant E
GE
Borgerding
Anthony J
AJ
Norby
Faye L
FL
Ren
Bonnie H
BH
Ye
Gang
G
Epstein
Paul N
PN
Ren
Jun
J
D000079:Acetaldehyde / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods; D018076:DNA, Complementary; D000431:Ethanol / Q000494:pharmacology*; D006321:Heart / Q000033:anatomy & histology; D006352:Heart Ventricles; D007668:Kidney / Q000033:anatomy & histology; D008099:Liver / Q000033:anatomy & histology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D018995:Myosin Heavy Chains / Q000235:genetics; D009929:Organ Size; D011401:Promoter Regions, Genetic
D018076:DNA, Complementary; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D018995:Myosin Heavy Chains; D000079:Acetaldehyde