Abstract 1100: Ppardelta is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart
PPARs (α, β and δ/β) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPARδ deficiency in mice leads to depressed myocardial fatty acid oxidation (FAO), bioenergetic and premature death with lipotoxic cardiomyopathy. To explore the role of PPARδ in the adult heart, we investigated the consequences of inducible short-term PPARδ knockout in the adult mouse heart. A substantial transcriptional downregulation of both FAO and fatty acid uptake proteins (by 30~60%) was revealed in the short-term PPARδ deficient adult heart, which was similar to those in the long-term PPARδ−/− heart. In addition, short-term PPARδ knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase (SOD1, by ~40%) and manganese superoxide dismutase (SOD2, by ~20%), leading to increased oxidative damage in the heart. Moreover, expressions of key mitochondrial biogenesis determinants such as PPARγ coactivator-1 (PGC-1α and -1β) were substantially decreased in the short-term PPARδ deficient heart, concomitant with decreased mitochondrial DNA copy number (by ~40%). Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPARδ knockout hearts. Consequently, PPARδ deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy. We suggest that PPARδ is an essential regulator of cardiac mitochondrial protection and biogenesis and that PPARδ activation can be a potential therapeutic target for cardiac disorders.