Very-long-chain acyl-coenzyme a dehydrogenase deficiency in mice

TitleVery-long-chain acyl-coenzyme a dehydrogenase deficiency in mice
Publication TypeJournal Article
Year of Publication2003
AuthorsExil VJ, Roberts RL, Sims H, McLaughlin JE, Malkin RA, Gardner CD, Ni G, Rottman JN, Strauss AW
JournalCirculation Research
Volume93
Issue5
Start Page448
Pagination448 - 455
Date Published01/2003
Abstract

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 γ 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.

DOI10.1161/01.RES.0000088786.19197.E4
Short TitleCirculation Research