Acetaldehyde and alcoholic cardiomyopathy: lessons from the ADH and ALDH2 transgenic models.
Alcoholic cardiomyopathy is manifested as ventricular dysfunction although its pathogenesis remains obscure. The major ethanol metabolite acetaldehyde is suspected to play a culprit role in the onset of this myopathic state. To explore the role of acetaldehyde in alcoholic cardiomyopathy, we generated transgenic mice with overexpression of the alcohol-metabolizing enzyme alcohol dehydrogenase (ADH) and the acetaldehyde-metabolizing enzyme mitochondrial aldehyde dehydrogenase (ALDH2), driven by myosin heavy chain and chicken beta-actin promoters, respectively. While neither transgene overtly affected the phenotype and intrinsic cardiomyocyte contractile properties of the background FVB mice, they altered the course of chronic alcohol ingestion-elicited alcoholic cardiomyopathy. Following an 8-12 week feeding with 4% alcoholic diet, cardiomyocyte mechanical function was depressed in FVB cardiomyocytes characterized by reduced peak shortening, impaired myocyte relengthening, and dampened intracellular Ca2+ release and sarcoplasmic reticulum Ca2+ re-uptake. This was associated with enhanced oxidative stress, lipid peroxidation and protein carbonyl formation in alcohol consuming FVB mice. Strikingly, ADH exaggerated whereas ALDH2 attenuated alcohol-induced mechanical and intracellular Ca2+ defects, oxidative stress, lipid peroxidation and protein damage. These data revealed that enhanced acetaldehyde production may be detrimental whereas facilitated acetaldehyde breakdown may be beneficial to alcoholic cardiomyopathy, indicating a possible therapeutic target against acetaldehyde in alcoholic tissue damage.
Ren
Jun
J
Centerfor Cardiovascular Research and Alternative Medicne, University of Wyoming, 1000 E. University Avenue, Department 3375, Laramie, WY 82071, USA.
D000079:Acetaldehyde / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002310:Cardiomyopathy, Alcoholic / Q000235:genetics* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects
D000426:Alcohol Dehydrogenase; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000079:Acetaldehyde; D002118:Calcium