Abstract 1819: Co-Upregulation of Peroxisome Proliferator-Activated Receptor-Alpha (PPARalpha) and Silent Information Regulator 1 (Sirt1) Negatively Regulates Cardiac Function Under Pressure Overload Induced Heart Failure
Cardiac overexpression of peroxisome proliferator-activated receptor-α (PPARα) mimics diabetic cardiomyopathy characterized by hypertrophy and intracellular accumulation of lipid, termed lipotoxicity. Sirt1 is a longevity factor, which induces deacetylation of proteins involved glucose and fat metabolism. Since Sirt1 mobilizes fat from other cell types, Sirt1 may alleviate PPARα-induced lipotoxic cardiomyopathy. Transverse aortic construction (TAC) induces upregulation of Sirt1 (2.7 fold vs sham) and PPARα (7.8 fold) in the heart, suggesting that co-upregulation of these genes takes place under pressure overload. To examine functional outcomes of co-upregulation of Sirt1 and PPARα, we crossed cardiac specific Sirt1 mice (Tg-Sirt1) and PPARα mice (Tg-PPARα). Tg-Sirt1 exhibited normal cardiac phenotype, whereas Tg-PPARα mild cardiac hypertrophy and dysfunction. Unexpectedly, Tg-Sirt1/Tg-PPARα bigenic mice exhibited severe cardiac hypertrophy (heart weight/body weight mg/g, Wild 4.5, Tg-Sirt1 4.6, Tg-PPAR 6.1, bigenic 9,2* (p<0.01 vs Tg-PPAR)) and heart failure (ejection fraction: control Wild 74%, Tg-Sirt1 73%, Tg-PPARα 64%, bigenic 27%* (p<0.01 vs Wild)). Some PPARα target genes, such as cpt1, mcad, glut4 and fatcd36, but not others, such as pgc-1α and fabp, was significantly downregulated in bigenic mice compared with those in Tg-PPARα Consistent with the suppression of fatcd36 expression (−75% vs Tg-PPRA; P<0.05), lipid accumulation was significantly attenuated in bigenic mice compared with Tg-PPARα as determined by the cardiac triglyceride content (nmol/μg protein; Wild 8.1, Tg-Sirt1 7.7 , Tg-PPAR 11.8, Bigenic 6.5, n=4). In cultured cardiac myocytes, Sirt1, but not catalytically inactive Sirt1, reduced the activity of PPARα-dependent reporter gene (−58%, p<0.05), suggesting that Sirt1 prevents PPARα-mediated gene transcription. These results suggest that Sirt1 partially inhibits PPARα-mediated gene transcription, thereby reducing fat accumulation, namely lipotoxicity, in cardiac myocytes. However, co-upregulation of Sirt1 and PPARα induces severe hypertrophy and failure in the mouse heart through lipotoxicity-independent mechanisms, and may contribute to cardiac dysfunction by pressure overload.
This research has received full or partial funding support from the American Heart Association, AHA National Center.