Abstract 1228: Peroxisome Proliferator-Activated Receptor γ regulating MnSOD Expression is Essential to Maintain Myocardial Redox Homeostasis
Peroxisome Proliferator-Activated Receptors (PPARα, δandγ) are ligand-activated nuclear receptors central to the transcriptional regulation of adipogenesis, glucose control and lipid metabolism. PPARα and PPARδ are important transcriptional regulators of fatty acid oxidation in the heart. However, the function of PPARγ in the heart remains obscure. To investigate the tissue specific role of PPARγ in the heart, a cardiomyocyte-restricted PPARγ knockout mouse line (CR-PPARγ− /−) was generated by crossing a α-MyHC-Cre with a floxed PPARγ mouse line. The first 2 exons of mouse PPARγ gene were targeted specifically in the hearts of CR-PPARγ−/− mice. CR-PPARγ− /− mice appeared to be normal after birth until they reached adulthood. However, expression of Sod2, (encoding manganese superoxide dismutase; MnSOD), a mitochondrial antioxidant enzyme was decreased by about 40% both in transcript and protein levels in cardiac samples from young CR-PPARγ− /− hearts without major pathological changes compared with those of controls (n=6, P<0.05), respectively. A functional PPAR response element in the Sod2 promoter was identified by promoter analyses and chromatin immuno-precipitation assays in cultured myocytes. MnSOD deficiency in young CR-PPARγ− /− hearts lead to about 32% decreased aconitase activities than those of controls (n=6, P<0.01). Quantitative analysis of immunoblots revealed approximately 35% less complex I protein abundance in CR-PPARγ− /− hearts than in comparable control samples (n=4, P<0.01). Mitochondria membrane potential was also depressed in CR-PPARγ− /− hearts by 24% relative to those of controls (n=6, P<0.05). Electronic microscope examinations revealed progressive mitochondrial damages in CR-PPARγ− /− hearts. In vivo hemodynamic measurements revealed that maximal and minimal dp/dt were depressed by 14% and 25%, respectively, in CR-PPARγ− /−mice compared with controls (n=6, P<0.05). As a result, adult CR-PPARγ− /− mice showed cardiac hypertrophy, progressive heart failure and premature dead. Taken together, this study shows that PPARγ regulates Sod2 transcription and serves as a crucial determinant of myocardial redox homeostasis.