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

Guoliang Ding, Mingui Fu, Qianhong Qin, William Lewis, Ha Won Kim, Tohru Fukai, Methode Bacanamwo, Yuqing Eugene Chen, Michael D. Schneider, David J. Mangelsdorf, Ronald M. Evans, Qinglin Yang

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Objectives: Peroxisome proliferator-activated receptors (PPAR) α and β/δ are essential transcriptional regulators of fatty acid oxidation in the heart. However, little is known about the roles of PPARγ in the heart. The present study is to investigate in vivo role(s) of PPARγ in the heart. Methods: A Cre-loxP mediated cardiomyocyte-restricted PPARγ knockout line was investigated. In these mice, exon 1 and 2 of PPARγ were targeted to eliminate PPARγ from cardiomyocytes. Results: PPARγ 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 PPARγ knockout mice independent of pathological changes. Promoter analyses revealed that Sod2 is a target gene of PPARγ. Consequently, myocardial superoxide content in PPARγ knockout mice was increased, leading to extensive oxidative damage. Treatment with a SOD mimetic compound, MnTBAP, prevented superoxide-induced cardiac pathological changes in PPARγ knockout mice. Conclusions: The present study demonstrates that PPARγ is critical to myocardial redox homeostasis. These findings should provide new insights into understanding the roles of PPARγ in the heart.

Original languageEnglish (US)
Pages (from-to)269-279
Number of pages11
JournalCardiovascular Research
Volume76
Issue number2
DOIs
StatePublished - Nov 1 2007

Keywords

  • Cardiac hypertrophy
  • Heart failure
  • Oxidative stress
  • PPARgamma
  • Sod2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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