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- Title
Cardiac peroxisome proliferator-activated receptor γ is essential in protecting cardiomyocytes from oxidative damage
- Authors
Ding, Guoliang; Fu, Mingui; Qin, Qianhong; Lewis, William; Kim, Ha Won; Fukai, Tohru; Bacanamwo, Methode; Chen, Yuqing Eugene; Schneider, Michael D.; Mangelsdorf, David J.; Evans, Ronald M.; Yang, Qinglin
- Abstract
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.
- Subjects
RODENTS; HEART diseases; CARDIAC hypertrophy; SUPEROXIDES
- Publication
Cardiovascular Research, 2007, Vol 76, Issue 2, p269
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1016/j.cardiores.2007.06.027