Abstract 20546: PPARalpha-Sirt1 Complex Downregulates Mitochondrial Gene Expression Through Suppression of the ERR Response Element in the Heart Under Pressure Overload
Mitochondrial dysfunction reduces energy production and increases oxidative stress and cell death. The molecular mechanism promoting mitochondrial dysfunction during heart failure (HF) is not fully understood. Pressure overload (PO) evoked by transverse aortic constriction significantly upregulated PPARα (7.8 fold vs sham) and Sirt1 (2.7 fold vs sham) in the mouse heart. PO-induced hypertrophy was attenuated in PPARα and Sirt1 heterozygous KO (PPARα+/− and Sirt1+/−) mice (heart weight/body weight (HW/BW, mg/g), Wild type (WT) 8.6, Sirt1+/− 6.9*, PPARα+/− 6.0*, p<0.05 vs WT), whereas co-expression of PPARα and Sirt1 (Tg-PPARα/Tg-Sirt1 bigenic mice) was sufficient to induce cardiac hypertrophy (HW/BW, WT 4.5, Tg-Sirt1 4.6, Tg-PPARα 6.1, bigenic 9.2*, p<0.01 vs Tg-PPARα) and cardiac dysfunction (ejection fraction, WT 74%, Tg-Sirt1 73%, Tg-PPARα 64%, bigenic 27%*, p<0.01 vs Tg-PPARα). Sirt1 was co-immunoprecipitated with PPARα, and co-expression of PPARα and Sirt1 significantly (p<0.05) downregulated genes involved in mitochondrial electron transport and ATP synthesis, including Ndufs1, Sdha and Atp5g1, known targets of estrogen related receptors (ERRs), and reduced mitochondrial ATP synthesis (−48% vs WT mice, p<0.05). The ERR response element (ERRE: TCAAGGTCA) contains a half core sequence of the PPAR response element (AGGTCANAGGTCA). Chromatin immunoprecipitation assays indicated that PPARα recruits Sirt1 and binds to the ERRE in the promoter of Ndufs1, Sdha and PGC1α. PPARα and Sirt1 cooperatively inhibited ERRE-mediated reporter gene activity, whereas Sirt1 knockdown normalized PPARα-mediated ERRE suppression in cardiac myocytes (siRNA Sirt1 1.02, PPARα 0.78*, siRNA Sirt1 plus PPARα 1.32*, Sirt1 0.91, Sirt1 plus PPARα 0.53* fold, p<0.05 vs control), suggesting that Sirt1 plays an essential role in mediating PPARα-mediated suppression of the ERRE. Both PPARα and Sirt1 bind to and deacetylate the flanking region of the ERRE histone in the heart under PO. PO-induced downregulation of ERRE target genes was attenuated in both PPARα+/− and Sirt1+/− mice. These results suggest that PPARα and Sirt1 form a transcription suppressor complex recognizing the ERRE under PO, thereby downregulating mitochondrial genes during HF.
- Cardiac hypertrophy
- Heart failure
- Mitochondrial energetics, heart failure, arrhythmias
- Myocardial contraction
- © 2010 by American Heart Association, Inc.