Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage.
OBJECTIVE
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 PPARgamma in the heart. The present study is to investigate in vivo role(s) of PPARgamma in the heart.


METHODS
A Cre-loxP mediated cardiomyocyte-restricted PPARgamma knockout line was investigated. In these mice, exon 1 and 2 of PPARgamma were targeted to eliminate PPARgamma from cardiomyocytes.


RESULTS
PPARgamma 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 PPARgamma knockout mice independent of pathological changes. Promoter analyses revealed that Sod2 is a target gene of PPARgamma. Consequently, myocardial superoxide content in PPARgamma knockout mice was increased, leading to extensive oxidative damage. Treatment with a SOD mimetic compound, MnTBAP, prevented superoxide-induced cardiac pathological changes in PPARgamma knockout mice.


CONCLUSIONS
The present study demonstrates that PPARgamma is critical to myocardial redox homeostasis. These findings should provide new insights into understanding the roles of PPARgamma in the heart.
Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30310, USA.
Guoliang
G
Ding
Mingui
M
Fu
Qianhong
Q
Qin
William
W
Lewis
Ha Won
HW
Kim
Tohru
T
Fukai
Methode
M
Bacanamwo
Yuqing Eugene
YE
Chen
Michael D
MD
Schneider
David J
DJ
Mangelsdorf
Ronald M
RM
Evans
Qinglin
Q
Yang
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D006333:Heart Failure / Q000209:etiology; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D008665:Metalloporphyrins; D016328:NF-kappa B; D047495:PPAR gamma; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin