Abstract 18251: Sirt1 Mediates Pressure Overload-Induced Cardiac Hypertrophy and Failure in vivo

Abstract

Mitochondrial dysfunction is a hallmark of the failing heart. Sirt1, a class III histone deacetylase, plays an important role in mediating transcriptional regulation of metabolic genes in response to stress. The function of endogenous Sirt1 during heart failure is poorly understood. Here we investigated the role of Sirt1 in pressure overload-induced cardiac hypertrophy and failure using genetically altered mouse models, namely cardiac specific Sirt1 heterozygous (Sirt1 +/- ) and homozygous (Sirt1 -/- ) knockout (KO) (C57BL/6) and Sirt1 overexpression (Tg-Sirt1) mice (FVB). These mice were subjected to pressure overload with transverse aortic constriction (TAC). Notably, C57BL/6 mice are more susceptible to TAC-induced cardiac hypertrophy and failure than FVB mice. Cardiac hypertrophy induced by 4 weeks of TAC was exacerbated in Tg-Sirt1 (heart weight/body weight (HW/BW, mg/g), Wild type (WT) 6.0, Tg-Sirt1 8.4*, p<0.05 vs WT), whereas it was ameliorated in Sirt1 KO mice (HW/BW, (mg/g), WT 7.9, Sirt1 +/- 6.9*, Sirt1 -/- 6.0*, * p<0.05 vs WT). TAC-induced systolic dysfunction was also exacerbated in Tg-Sirt1 (ejection fraction (EF) (%), WT 71, Tg-Sirt1 48*, p<0.05 vs WT), whereas it was ameliorated in Sirt1 KO mice (EF (%), WT 55, Sirt1 +/- 65*, Sirt1 -/- 63*, * p<0.05 vs WT). The expression of nuclear encoded mitochondrial genes, such as Cpt2, Sdha, Fh1 and Ndufv1, was downregulated by TAC in WT mice, an effect that was normalized in Sirt1 -/- mice (relative mRNA levels vs WT sham, Sdha: WT TAC 0.56, Sirt1 -/- sham 1.2, Sirt1 -/- TAC 0.81*, Ndufv1: WT TAC 0.59, Sirt1 -/- sham 0.84, Sirt1 -/- TAC 1.1*, * p<0.05 vs WT TAC). On the other hand, ATP content was decreased in Tg-Sirt1 mice after TAC (45% reduction vs WT). Chromatin immunoprecipitation assays revealed that pressure overload induces recruitment of Sirt1 to the promoter region of these mitochondrial genes (relative promoter occupancy after 4 weeks of TAC, Cpt2 2.6*, Sdha 7.4*, Fh1 5.4*, Ndufv1 5.6*, * p<0.05 vs sham), indicating that endogenous Sirt1 interacts with mitochondrial genes, thereby negatively regulating their expression during TAC. These results suggest that Sirt1 mediates pressure overload-induced cardiac hypertrophy and failure, possibly through attenuation of mitochondrial function.