title: Cardiac overexpression of alcohol dehydrogenase exacerbates cardiac contractile dysfunction, lipid peroxidation, and protein damage after chronic ethanol ingestion.
abstract: BACKGROUND
  Alcoholic cardiomyopathy is manifested as ventricular dysfunction, although its specific toxic mechanism remains obscure. This study was designed to examine the impact of enhanced acetaldehyde exposure on cardiac function via cardiac-specific overexpression of alcohol dehydrogenase (ADH) after alcohol intake.
  
  
  METHODS
  ADH transgenic and wild-type FVB mice were placed on a 4% alcohol or control diet for 8 weeks. Mechanical and intracellular Ca2+ properties were evaluated in cardiac myocytes. Levels of acetaldehyde, lipid peroxidation, and protein carbonyl formation were determined.
  
  
  RESULTS
  FVB and ADH mice consuming ethanol exhibited elevated blood ethanol/acetaldehyde, cardiac acetaldehyde, and cardiac hypertrophy compared with non-ethanol-consuming mice. However, the levels of cardiac acetaldehyde and hypertrophy were significantly greater in ADH ethanol-fed mice than FVB ethanol-fed mice. ADH transgene itself did not affect mechanical and intracellular Ca2+ properties with the exception of reduced resting intracellular Ca2+ and Ca2+ re-sequestration at low pace frequency. Myocytes from ethanol-fed mice showed significantly depressed peak shortening, velocity of shortening/relengthening, rise of intracellular Ca2+ transients, and sarco(endo)plasmic reticulum Ca2+ load associated with similar duration of shortening/relengthening compared with myocytes from control mice. Strikingly, the ethanol-induced mechanical and intracellular Ca2+ defects were exacerbated in ADH myocytes compared with the FVB group except velocity of shortening/relengthening. The lipid peroxidation end products malondialdehyde and protein carbonyl formation were significantly elevated in both livers and hearts after chronic ethanol consumption, with the cardiac lipid and protein damage being exaggerated by ADH transgene.
  
  
  CONCLUSIONS
  These data suggest that increased cardiac acetaldehyde exposure due to ADH transgene may play an important role in cardiac contractile dysfunctions associated with lipid and protein damage after alcohol intake.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, Grand Forks, USA.
authors.forename: Kadon K
authors.initials: KK
authors.lastname: Hintz
authors.forename: David P
authors.initials: DP
authors.lastname: Relling
authors.forename: Jack T
authors.initials: JT
authors.lastname: Saari
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Borgerding
authors.forename: Jinhong
authors.initials: J
authors.lastname: Duan
authors.forename: Bonnie H
authors.initials: BH
authors.lastname: Ren
authors.forename: Kosai
authors.initials: K
authors.lastname: Kato
authors.forename: Paul N
authors.initials: PN
authors.lastname: Epstein
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000426:Alcohol Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D000431:Ethanol / Q000008:administration & dosage*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D011506:Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; D000431:Ethanol; D000426:Alcohol Dehydrogenase