Cardiac peroxisome proliferator-activated receptor γ is essential in protecting cardiomyocytes from oxidative damage

Objectives: Peroxisome proliferator-activated receptors (PPAR) alpha and (beta/delta are essential transcriptional regulators of fatty acid oxidation in the heart. However, little is known about the roles of PPAR gamma in the heart. The present study is to investigate in vivo role(s) of PPAR gamma in the heart. Methods: A Cre-loxP mediated cardiomyocyte-restricted PPAR gamma knockout line was investigated. In these mice, exon 1 and 2 of PPAR(gamma) were targeted to eliminate PPAR gamma from cardiomyocytes. Results: PPAR gamma null mice exhibited pathological changes around 3 months of age, featuring progressive cardiac hypertrophy with mitochondrial oxidative damage. Most mice died from dilated cardiomyopathy. Cardiac expression of Sod2 (encoding manganese superoxide dismutase; MnSOD), a mitochondrial antioxidant enzyme was downregulated both in transcript and protein levels in cardiac samples in PPAR gamma knockout mice independent of pathological changes. Promoter analyses revealed that Sod2 is a target gene of PPAR gamma. Consequently, myocardial superoxide content in PPAR gamma knockout mice was increased, leading to extensive oxidative damage. Treatment with a SOD mimetic compound, MnTBAP, prevented superoxide-induced cardiac pathological changes in PPAR gamma knockout mice. Conclusions: The present study demonstrates that PPAR gamma is critical to myocardial redox homeostasis. These findings should provide new insights into understanding the roles of PPAR gamma in the heart. (C) 2007 European Society of Cardiology. Published by Elsevier B.V.