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  • Title: Downregulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity.
    Author: Dewald O, Sharma S, Adrogue J, Salazar R, Duerr GD, Crapo JD, Entman ML, Taegtmeyer H.
    Journal: Circulation; 2005 Jul 19; 112(3):407-15. PubMed ID: 16009788.
    Abstract:
    BACKGROUND: The peroxisome proliferators-activated receptor-alpha (PPARalpha), a transcription factor that modulates fatty acid metabolism, regulates substrate preference in the heart. Although in acute ischemia there is a switch in substrate preference from fatty acids to glucose, metabolic gene expression in repetitive ischemia is not well described. In a mouse model of ischemic cardiomyopathy induced by repetitive ischemia/reperfusion (I/R), we postulated that downregulation of PPARalpha is regulated by reactive oxygen species and is necessary for maintaining contractile function in the heart. METHODS AND RESULTS: Repetitive closed-chest I/R (15 minutes) was performed daily in C57/BL6 mice, mice overexpressing extracellular superoxide dismutase, and mice treated with the PPARalpha agonist-WY-14,643. Echocardiography, histology, and candidate gene expression were measured at 3, 5, 7, and 28 days of repetitive I/R and 15 and 30 days after discontinuation of I/R. Repetitive I/R was associated with a downregulation of PPARalpha-regulated genes and both myosin heavy chain isoform transcript levels, which was reversible on discontinuation of I/R. Overexpression of EC-SOD prevented the downregulation of PPARalpha-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPARalpha in mice exposed to repetitive I/R worsened contractile function, induced microinfarctions, and increased intramyocardial triglyceride deposition, features suggestive of cardiac lipotoxicity. CONCLUSIONS: Metabolic and myosin isoform gene expression in repetitive I/R is mediated by reactive oxygen species. Furthermore, we suggest that downregulation of PPARalpha in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.
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