Peroxisome Proliferator-Activated Receptor β/δ Activation in Adult Hearts Facilitates Mitochondrial Function and Cardiac Performance Under Pressure-Overload Condition

Abstract

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is an essential transcription factor in myocardial metabolism. This study aims to investigate the effects of PPARβ/δ activation in the adult heart on mitochondrial biology and oxidative metabolism under normal and pressure-overload conditions. We have investigated the effects of cardiac constitutively active PPARβ/δ in adult mice using a tamoxifen-inducible transgenic approach with Cre-LoxP recombination. The expression of PPARβ/δ mRNA and protein in cardiomyocytes of adult mice was substantially increased after short-term induction. In these mice, the cardiac expression of key factors involved in mitochondrial biogenesis, such as PPARγ coactivator-1, endogenous antioxidants Cu/Zn superoxide dismutase, and catalase, fatty acid, and glucose metabolism, such as carnitine palmitoyltransferase Ib, carnitine palmitoyltransferase II, and glucose transporter 4, were upregulated. Subsequently, myocardial oxidative metabolism was elevated concomitant with an increased mitochondrial DNA copy number and an enhanced cardiac performance. Moreover, activation of PPARβ/δ in the adult heart improved cardiac function and resisted progression to pathological development in mechanical stress condition. We conclude that PPARβ/δ activation in the adult heart will promote cardiac performance along with transcriptional upregulation of mitochondrial biogenesis and defense, as well as oxidative metabolism at basal and pressure-overload conditions.