title: Specific and sustained down-regulation of genes involved in fatty acid metabolism is not a hallmark of progression to cardiac failure in mice.
abstract: Preferential and specific down-regulation of genes involved in fatty acid (FA) uptake and metabolism is considered a hallmark of severe hypertrophic remodeling and progression to cardiac failure. Therefore, we investigated the time course of changes in cardiac metabolic gene expression (1) in mice subjected to regional myocardial infarction (MI) for 4 days, 1 month, or 3 months and (2) in mice overexpressing calcineurin (Cn) which initially develop concentric hypertrophy progressing after the age of 4 weeks to dilated cardiomyopathy and failure. In both models, hypertrophy was characterized by increased expression of beta-myosin heavy chain protein and atrial natriuretic factor mRNA, indicative of marked structural remodeling. Fractional shortening progressively decreased from 31% to 15.1% and 3.7% 1 and 3 months after MI, respectively. One month post-MI, the expression of several metabolic genes, i.e., acyl-CoA synthetase (-50%), muscle-type carnitine palmitoyl transferase 1 (-37%) and citrate synthase (-28%), was significantly reduced in the surviving myocardium. Despite overt signs of cardiac failure 3 months post-MI, the expression of these genes had returned to normal levels. In hearts of both 4- and 6-week-old Cn mice, genes involved in both FA and glucose metabolism and mitochondrial citrate synthase were down-regulated, reflecting an overall decline in metabolic gene expression, rather than a specific and preferential down-regulation of genes involved in FA uptake and metabolism. These findings challenge the concept that specific and sustained down-regulation of genes involved in FA uptake and metabolism represents a hallmark of the development of cardiac hypertrophy and progression to failure.
authors.affiliation: Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: K F J
authors.initials: KF
authors.lastname: de Brouwer
authors.forename: H
authors.initials: H
authors.lastname: Degens
authors.forename: W M
authors.initials: WM
authors.lastname: Aartsen
authors.forename: M
authors.initials: M
authors.lastname: Lindhout
authors.forename: N J J E
authors.initials: NJ
authors.lastname: Bitsch
authors.forename: A J
authors.initials: AJ
authors.lastname: Gilde
authors.forename: P H M
authors.initials: PH
authors.lastname: Willemsen
authors.forename: B J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: G J
authors.initials: GJ
authors.lastname: van der Vusse
authors.forename: M
authors.initials: M
authors.lastname: van Bilsen
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001835:Body Weight; D019703:Calcineurin / Q000235:genetics; D006332:Cardiomegaly / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics*; D004452:Echocardiography; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression; D006321:Heart / Q000502:physiology; D006333:Heart Failure / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000139:chemically induced; D018995:Myosin Heavy Chains / Q000235:genetics; D009929:Organ Size; D010084:Oxidation-Reduction; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D005227:Fatty Acids; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor; D019703:Calcineurin; D018995:Myosin Heavy Chains