Rationale: Clinical studies have shown that Sirt3 (Sirtuin 3) expression declines by 40% by 65 years of age paralleling the increased incidence of hypertension and metabolic conditions further inactivate Sirt3 because of increased NADH (nicotinamide adenine dinucleotide, reduced form) and acetyl-CoA levels. Sirt3 impairment reduces the activity of a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2) because of hyperacetylation.

Objective: In this study, we examined whether the loss of Sirt3 activity increases vascular oxidative stress because of SOD2 hyperacetylation and promotes endothelial dysfunction and hypertension.

Methods and Results: Hypertension was markedly increased in Sirt3-knockout (Sirt3^−/−) and SOD2-depleted (SOD2^+/−) mice in response to low dose of angiotensin II (0.3 mg/kg per day) compared with wild-type C57Bl/6J mice. Sirt3 depletion increased SOD2 acetylation, elevated mitochondrial O₂^· –, and diminished endothelial nitric oxide. Angiotensin II-induced hypertension was associated with Sirt3 S-glutathionylation, acetylation of vascular SOD2, and reduced SOD2 activity. Scavenging of mitochondrial H₂O₂ in mCAT mice expressing mitochondria-targeted catalase prevented Sirt3 and SOD2 impairment and attenuated hypertension. Treatment of mice after onset of hypertension with a mitochondria-targeted H₂O₂ scavenger, mitochondria-targeted hydrogen peroxide scavenger ebselen, reduced Sirt3 S-glutathionylation, diminished SOD2 acetylation, and reduced blood pressure in wild-type but not in Sirt3^−/− mice, whereas an SOD2 mimetic, (2-[2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino]-2-oxoethyl) triphenylphosphonium (mitoTEMPO), reduced blood pressure and improved vasorelaxation both in Sirt3^−/− and wild-type mice. SOD2 acetylation had an inverse correlation with SOD2 activity and a direct correlation with the severity of hypertension. Analysis of human subjects with essential hypertension showed 2.6-fold increase in SOD2 acetylation and 1.4-fold decrease in Sirt3 levels, whereas SOD2 expression was not affected.

Conclusions: Our data suggest that diminished Sirt3 expression and redox inactivation of Sirt3 lead to SOD2 inactivation and contributes to the pathogenesis of hypertension.

原理：临床研究表明，到65岁时，Sirt3（Sirtuin 3）的表达下降40％，与此同时，高血压和代谢状况的发生率也由于NADH（烟酰胺腺嘌呤二核苷酸，还原形式）和乙酰辅酶A的增加而进一步使Sirt3失活。水平。Sirt3损伤会因乙酰化过高而降低关键线粒体抗氧化酶超氧化物歧化酶2（SOD2）的活性。

目的：在这项研究中，我们检查了Sirt3活性的丧失是否由于SOD2过乙酰化而增加了血管氧化应激并促进了内皮功能障碍和高血压。

方法和结果：高血压SIRT3敲除显着增加（SIRT3 ^{- / -} ）和SOD2耗尽（SOD2 ^{+ / -} ）响应于与野生型相比，血管紧张素II（0.3mg / kg的每日）的低剂量的小鼠C57Bl / 6J小鼠。Sirt3的消耗增加了SOD2的乙酰化作用，增加了线粒体O ₂ ^·–的含量，并减少了内皮一氧化氮。血管紧张素II诱发的高血压与Sirt3 S-谷胱甘肽酰化，血管SOD2的乙酰化和SOD2活性降低有关。清除线粒体H ₂ O ₂表达线粒体靶向过氧化氢酶的mCAT小鼠体内，可预防Sirt3和SOD2损伤并减轻高血压。用线粒体靶向的H ₂ O ₂清除剂，线粒体靶向的过氧化氢清除剂ebselen，降低Sirt3 S-谷胱甘肽酰化，降低SOD2乙酰化和降低野生型（而非Sirt3 ^-/-）血压来治疗高血压后的小鼠⁻小鼠，而SOD2模拟物（2- [2,2,6,6-四甲基哌啶-1-氧基-1--4-氨基氨基] -2-氧代乙基）三苯基phosph（mitoTEMPO）降低了血压并改善了Sirt3的血管舒张作用^{- /-}和野生型小鼠。SOD2乙酰化与SOD2活性成反比，与高血压严重程度成正比。对患有原发性高血压的人类受试者的分析显示，SOD2乙酰化水平提高2.6倍，Sirt3水平降低1.4倍，而SOD2表达未受影响。

结论：我们的数据表明，Sirt3表达的降低和Sirt3的氧化还原失活导致SOD2失活，并有助于高血压的发病机理。