Abstract 15326: Inactivation of Mitochondrial Deacetylase Sirt3 Induces Oxidative Stress, Promotes Vascular Hypertrophy, Increases Aortic Dissections, Exacerbates Hypertension and Mortality

Abstract

Introduction: Vascular dysfunction plays a key role in hypertension and cardiovascular disease, which causes one-third of deaths worldwide. Mitochondrial dysfunction contributes to these conditions; however, specific mechanisms are not clear. We showed inactivation of mitochondrial deacetylase Sirt3 in arterioles from patients with essential hypertension associated with superoxide dismutase inactivation, vascular inflammation and oxidative stress. Hypothesis: We hypothesized that the loss of vascular Sirt3 induces oxidative stress, promotes vascular dysfunction and hypertension. Methods: To test this hypothesis, we developed tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (SmcSirt3KO) by crossing the Sirt3flox/flox mice with mice carrying a gene for inducible Cre in the vascular smooth muscle cells. Results and Discussion: Hypertension was modestly increased but considerably increased mortality in angiotensin II-infused SmcSirt3KO mice (35% vs 5% in WT) which was associated with higher rate of aortic dissections (50% vs 10% in WT). The basal superoxide and nitric oxide levels were not affected in SmcSirt3KO mice, however, angiotensin II infusion significantly increased superoxide and nitric oxide inactivation in SmcSirt3KO mice compared with wild-type mice supporting the pathological role of smooth muscle Sirt3 impairment. Post-mortem analysis showed high frequency of abdominal aortic aneurysms in angiotensin II-infused SmcSirt3KO mice suggesting that adverse vascular remodeling contributed to high mortality in these mice. To gain further insight into vascular pathology we performed histological examination using Verhoeff-van Gieson staining. Angiotensin II-infused SmcSirt3KO mice had 5-time higher abdominal aortic dissections rate, increased vascular hypertrophy, and disrupted elastic lamellae. Conclusion: Aortic dissection is a catastrophic disease with high mortality and morbidity characterized by fragmentation of elastin and smooth muscle cell dysfunction. Our data suggest that Sirt3 impairment can contribute to vascular hypertrophy, aortic dissection, end-organ-damage and mortality. It is conceivable that targeting Sirt3 may have therapeutic potential in cardiovascular disease.