A transgenic model of acetaldehyde overproduction accelerates alcohol cardiomyopathy.
Chronic alcohol consumption produces alcoholic heart muscle disease (AHMD), a prevalent form of congestive heart failure. Several hypotheses have been proposed to explain the damaging effects of alcohol on the heart, but neither the mechanism nor the ultimate toxin has been established. In this study, we use transgenic overexpression of alcohol dehydrogenase to elevate cardiac exposure to acetaldehyde, the major and most reactive metabolite of alcohol. Overexpression of alcohol dehydrogenase by 40-fold produced no detectable deleterious effects to the heart in the absence of alcohol. In the presence of alcohol, transgenic hearts contained 4-fold higher acetaldehyde than control hearts. Chronic alcohol exposure produced many changes similar to AHMD in transgenic hearts. Compared with control hearts, these pathological changes occurred more rapidly and to a greater extent: alcohol-exposed transgenic hearts were almost twice as large as control hearts. They demonstrated ultrastructural damage consistent with AHMD and had much lower contractility than alcohol-exposed control hearts. In addition, the transgenic hearts showed greater changes in mRNA expression for alpha-skeletal actin and atrial natriuretic factor than alcohol-exposed control hearts. Alterations in NAD(+)/NADH levels were insufficient to account for such severe damage in cardiomyopathic hearts. The increased damage produced in transgenic hearts suggests an important role for acetaldehyde in AHMD.
Liang
Q
Q
Department of Pharmacology and Toxicology, University of North Dakota, Grand Forks, North Dakota 58203, USA.
Carlson
E C
EC
Borgerding
A J
AJ
Epstein
P N
PN
D000079:Acetaldehyde / Q000378:metabolism*; D000199:Actins / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000139:chemically induced; D002310:Cardiomyopathy, Alcoholic / Q000209:etiology*; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000187:drug effects; D009243:NAD / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors
D000199:Actins; D012333:RNA, Messenger; D009243:NAD; D000431:Ethanol; D009320:Atrial Natriuretic Factor; D007770:L-Lactate Dehydrogenase; D000079:Acetaldehyde