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Peroxisome Proliferator Activated Receptor (PPAR) Agonists Inhibit Hypertrophy of Neonatal Rat Cardiac Myocytes

Department of Medicine (D.G.D.) and Diabetes Center (F.L., F.W., S.Z., D.G.D.), University of California at San Francisco, San Francisco, California 94143-0540

Address all correspondence and requests for reprints to: David G. Gardner, Diabetes Center, University of California at San Francisco, 1109 HSW, 513 Parnassus Avenue, San Francisco, California 94143-0540. E-mail: gardner{at}itsa.ucsf.edu.

The peroxisome proliferator activated receptors (PPARs) appear to have beneficial effects in the cardiovascular system. PPAR has been shown previously to exert an inhibitory effect on cardiac myocyte hypertrophy in vivo and in vitro. Using endothelin to activate the hypertrophic program in neonatal rat cardiac myocytes, we demonstrate that PPAR ligands (fenofibrate and WY14,643) suppress hypertrophy-dependent increases in protein synthesis, cell surface area, and sarcomeric organization in vitro. This was accompanied by a decrease in brain natriuretic peptide gene expression, a marker of transcriptional activation in hypertrophy. These effects were equivalent to or greater than those seen with the PPAR agonist rosiglitazone. Fenofibrate and rosiglitazone suppressed endothelin stimulation of human brain natriuretic peptide gene promoter activity, and this effect was amplified by cotransfection of PPAR and PPAR expression vectors, respectively. The fenofibrate-dependent suppression of endothelin’s stimulatory activity was dependent upon promoter sequence positioned between -904 and -40 relative to the transcription start site and did not appear to involve a number of positive and negative regulatory elements that are known to govern transcription of this gene. These findings suggest that PPAR ligands could prove to be useful in the management of disorders associated with hypertrophy and remodeling of the myocardium.

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