Published online before print July 31, 2003, doi: 10.1161/01.RES.0000088786.19197.E4
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© 2003 American Heart Association, Inc.
Integrative Physiology |
Very-Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency in Mice
From the Division of Cardiology, Department of Pediatrics (V.J.E., C.D.G., A.W.S), Department of Pathology (R.L.R.), Division of Cardiovascular Medicine, Department of Internal Medicine and Mouse Metabolic Phenotyping Center (G.N., J.N.R.), Vanderbilt University School of Medicine, Nashville, Tenn; Department of Pediatrics, Division of Pediatric Cardiology (H.S.), Washington University School of Medicine, St Louis, Mo; Joint Program in Biomedical Engineering (J.E.M., R.A.M.); University of Memphis and University of Tennessee Health Sciences Center, Memphis, Tenn.
Correspondence to Dr Vernat Exil, Vanderbilt Children’s Hospital, 1161 21st Ave South, D-2220 MCN, Nashville, TN 37232. E-mail vernat.exil{at}vanderbilt.edu
Fatty acid oxidation (FAO) defects are inborn errors of metabolism clinically associated with cardiomyopathy and sudden infant death syndrome (SIDS). FAO disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to stresses such as fasting, exercise, or intercurrent viral illness. It is uncertain whether the heart, in the absence of stress, is normal. We generated very-long-chain acyl-coenzyme A dehydrogenase (VLCAD)-deficient mice by homologous recombination to define the onset and molecular mechanism of myocardial disease. We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthase (ACS1), adipophilin, activator protein 2, cytochrome c, and the peroxisome proliferator activated receptor 
coactivator-1 were increased immediately after birth, preceding overt histological lipidosis, whereas ACS1 expression was markedly downregulated in the adult heart. We conclude that mice with VLCAD deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiological correlates of the associated human disease in the absence of stress.
Key Words: inborn error of metabolism • mitochondrial ß-oxidation • cardiac lipidosis • ventricular arrhythmias • sudden infant death syndrome
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