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Cardiovascular Research 2007 76(2):269-279; doi:10.1016/j.cardiores.2007.06.027
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Copyright © 2007, European Society of Cardiology

Cardiac peroxisome proliferator-activated receptor {delta} is essential in protecting cardiomyocytes from oxidative damage

Guoliang Dinga, Mingui Fub, Qianhong Qina, William Lewisc, Ha Won Kimd, Tohru Fukaid, Methode Bacanamwoa, Yuqing Eugene Chene, Michael D. Schneiderf, David J. Mangelsdorfb, Ronald M. Evansg and Qinglin Yanga,*

aCardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30310, United States
bHoward Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, United States
cDepartment of Pathology and Laboratory Medicine, Emory University, 101 Woodruff Circle, Room 7117, Atlanta, GA 30322, United States
dDivision of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States
eCardiovascular Center, University of Michigan Medical Center, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, United States
fCenter for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
gHoward Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States

*Corresponding author. Tel.: +1 404 756 5056; fax: +1 404 752 1042. qyang{at}msm.edu

Objectives Peroxisome proliferator-activated receptors (PPAR) {alpha} and β/{delta} are essential transcriptional regulators of fatty acid oxidation in the heart. However, little is known about the roles of PPAR{delta} in the heart. The present study is to investigate in vivo role(s) of PPAR{delta} in the heart.

Methods A Cre–loxP mediated cardiomyocyte-restricted PPAR{delta} knockout line was investigated. In these mice, exon 1 and 2 of PPAR{delta} were targeted to eliminate PPAR{delta} from cardiomyocytes.

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

Conclusions The present study demonstrates that PPAR{delta} is critical to myocardial redox homeostasis. These findings should provide new insights into understanding the roles of PPAR{delta} in the heart.

KEYWORDS PPARgamma; Sod2; Oxidative stress; Cardiac hypertrophy; Heart failure


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