Abstract P345: Overexpression of Mitochondrial Deacetylase Sirt3 Protects Endothelial Function and Attenuates Hypertension While Sirt3 Depletion Increases Oxidative Stress and Endothelial Dysfunction Due to SOD2 Hyperacetylation

Abstract

We have recently reported SOD2 hyperacetylation and reduced Sirt3 level in human subjects with essential hypertension. We hypothesized that diminished Sirt3 expression promotes endothelial dysfunction and hypertension while Sirt3 overexpression protects endothelial function and attenuates hypertension. Indeed, hypertension was markedly increased in Sirt3 knockout (Sirt3 -/- ) in response to angiotensin II (0.7 mg/kg/day) compared with wild-type C57Bl/6J mice. Sirt3 depletion caused SOD2 inactivation due to SOD2 hyperacetylation, increased mitochondrial O 2 • and diminished endothelial nitric oxide. Angiotensin II infusion in wild-type mice was associated with Sirt3 inactivation and SOD2 hyperacetylation in aorta and kidney. To test the specific role of Sirt3 in vasculature we have generated tamoxifen-inducible endothelium specific Sirt3 knockout mice (Ec Sirt3 KO ) and tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (Smc Sirt3 KO ). Deletion of Sirt3 in smooth muscle exacerbated hypertension (165 mm Hg vs 155 mm Hg in wild-type) and significantly increased mortality in angiotensin II infused Smc Sirt3 KO mice (30% vs 3% in wild-type) which was associated with higher rate of aortic aneurysm. Ec Sirt3 KO mice had elevated basal blood pressure by 12 mm Hg and hypertension was exacerbated in Ec Sirt3 KO mice accompanied by impaired vascular relaxation and reduced endothelial nitric oxide. Treatment of angiotensin II-infused Sirt3 -/- mice with SOD2 mimetic mitoTEMPO rescued endothelial-dependent relaxation and reduced blood pressure. We tested if Sirt3 overexpression protects endothelial function and attenuates angiotensin II-induced hypertension. These new mice were obtained by crossing the EIIa-cre with Sirt3flox mice resulting in constitutively increased Sirt3 in the whole body. Sirt3 overexpression abolished angiotensin II induced impairment of vasorelaxation and attenuated development of hypertension. Our data suggest that diminished Sirt3 activity leads to SOD2 hyperacetylation and contributes to the pathogenesis of hypertension. It is conceivable that Sirt3 agonists and SOD2 mimetics may have therapeutic potential in cardiovascular disease.