Acetaldehyde and alcoholic cardiomyopathy: lessons from the ADH and ALDH2 transgenic models.

Abstract

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.

• Authors: Jun Ren
• Journal: Novartis Foundation symposium (Novartis Found Symp) Vol. 285 Pg. 69-76; discussion 76-9, 198-9 ( 2007) ISSN: 1528-2511 [Print] England
• PMID: 17590987 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Alcohol Dehydrogenase
• ALDH2 protein, human
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial
• Acetaldehyde
• Calcium

Topics

• Acetaldehyde (blood, metabolism, toxicity)
• Alcohol Dehydrogenase (genetics, metabolism)
• Aldehyde Dehydrogenase (genetics, metabolism)
• Aldehyde Dehydrogenase, Mitochondrial
• Animals
• Calcium (metabolism)
• Cardiomyopathy, Alcoholic (genetics, physiopathology)
• Disease Models, Animal
• Gene Transfer Techniques
• Lipid Peroxidation (drug effects)
• Mice
• Mice, Transgenic
• Myocytes, Cardiac (drug effects, metabolism, physiology)
• Oxidative Stress (drug effects)
• Protein Carbonylation (drug effects)