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Specific and sustained down-regulation of genes involved in fatty acid metabolism is not a hallmark of progression to cardiac failure in mice

Brouwer, Kristel F.J. de and Degens, Hans and Aartsen, Wendy M. and Lindhout, Martijn and Bitsch, Nicole J.J.E. and Gilde, Andreis J. and Willemsen, Peter H.M. and Janssen, Ben J. and Vusse, Ger J. van der and Bilsen, Marc van (2006) Specific and sustained down-regulation of genes involved in fatty acid metabolism is not a hallmark of progression to cardiac failure in mice. Journal of molecular and cellular cardiology, 40 (6). pp. 838-845. ISSN 0022-2828

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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 β-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. Abbreviations: ACS, acyl-CoA synthetase; ANF, atrial natriuretic factor; BM, body mass; Cn, calcineurin; CS, citrate synthase; EF, ejection fraction; FA, fatty acid; FAT/CD36, fatty acid translocase; FS, fractional shortening; GLUT4, glucose transporter-4; H-FABP, heart-type fatty-acid-binding protein; HKII, hexokinase II; HM, heart mass; LCAD, long-chain acyl-CoA dehydrogenase; LiM, liver mass; LuM, lung mass; LV, left ventricle; mCPT-1, muscle-type carnitine palmitoyl transferase 1; MHC, myosin heavy chain; MI, myocardial infarction; PPAR, peroxisome-proliferator-activated receptor; SV, stroke volume

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