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

doi:10.1016/j.cardiores.2007.06.027

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

^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

Received April 11, 2007.
Revision requested June 23, 2007.
Accepted June 27, 2007.

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 PPARδ in the heart. The present study is to investigate in vivo role(s) of PPARδ in the heart.

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

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

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

Keywords