Published Online
on July 11, 2005

A more recent version of this article appeared on July 19, 2005

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Submitted on January 14, 2005
Revised on March 1, 2005
Accepted on April 5, 2005

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, and 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.).

^* To whom correspondence should be addressed. E-mail: Heinrich.Taegtmeyer{at}uth.tmc.edu.

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.

Key words: free radicals • hibernation • ischemia • metabolism • reperfusion

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