Peroxisome Proliferator-Activated Receptor δ Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart

Rationale: Peroxisome proliferator-activated receptors (PPARs) (alpha, gamma, and delta/beta) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPAR delta deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy. Objective: To explore the essential role of PPAR delta in the adult heart. Methods and Results: We investigated the consequences of inducible short-term PPAR delta knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPAR delta knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPAR gamma coactivator-1 were substantially decreased in the short-term PPAR delta deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPAR delta knockout hearts. Consequently, PPAR delta deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy. Conclusions: PPAR delta is an essential regulator of cardiac mitochondrial protection and biogenesis and PPAR delta activation can be a potential therapeutic target for cardiac disorders. (Circ Res. 2010; 106: 911-919.)