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(Circulation. 2005;112:407-415.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Downregulation of Peroxisome Proliferator–Activated Receptor- Gene Expression in a Mouse Model of Ischemic Cardiomyopathy Is Dependent on Reactive Oxygen Species and Prevents Lipotoxicity

Oliver Dewald, MD^*; Saumya Sharma, MD^*; Julia Adrogue, MD; Rebecca Salazar, BS; Georg D. Duerr, BS; James D. Crapo, MD; Mark L. Entman, MD; Heinrich Taegtmeyer, MD, DPhil

From the Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, Houston (S.S., J.A., R.S., H.T.); Cardiovascular Sciences and DeBakey Heart Center, Baylor College of Medicine and the Methodist Hospital, Houston, Texas (O.D., G.D.D., M.L.E.); Department of Cardiac Surgery, University Clinical Center Bonn, Bonn, Germany (O.D.); and Department of Medicine, National Jewish Medical and Research Center, Denver, Colo (J.D.C.).

Correspondence to Heinrich Taegtmeyer, MD, DPhil, Department of Internal Medicine, Division of Cardiology, University of Texas Houston Medical School, 6431 Fannin St, MSB 1.246, Houston, TX 77030. E-mail Heinrich.Taegtmeyer{at}uth.tmc.edu

Received January 14, 2005; revision received March 1, 2005; accepted April 5, 2005.

Background— The peroxisome proliferators–activated receptor- (PPAR), 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 PPAR 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 PPAR 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 PPAR-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 PPAR-regulated genes and myosin iso-genes by repetitive I/R. Furthermore, reactivation of PPAR 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 PPAR in repetitive I/R is an adaptive mechanism that is able to prevent lipotoxicity in the ischemic myocardium.

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