Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Am J Physiol Heart Circ Physiol. 2024 Aug 1;327(2):H433-H443. doi: 10.1152/ajpheart.00162.2024. Epub 2024 Jun 21.
Almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite the use of multiple drugs, likely because of mechanisms that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. Hypertension is associated with inactivation of key intrinsic mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to hyperacetylation, but the role of specific SOD2 lysine residues has not been defined. Hypertension is associated with SOD2 acetylation at lysine 68, and we suggested that deacetylation mimetic mutation of K68 to arginine in SOD2 inhibits vascular oxidative stress and attenuates hypertension. To test this hypothesis, we have developed a new deacetylation mimetic SOD2-K68R mice. We performed in vivo studies in SOD2-K68R mice using angiotensin II (ANG II) model of vascular dysfunction and hypertension. ANG II infusion in wild-type mice induced vascular inflammation and oxidative stress and increased blood pressure to 160 mmHg. SOD2-K68R mutation completely prevented increase in mitochondrial superoxide, abrogated vascular oxidative stress, preserved endothelial nitric oxide production, protected vasorelaxation, and attenuated ANG II-induced hypertension. ANG II and cytokines contribute to vascular oxidative stress and hypertension. Treatment of wild-type aortas with ANG II and cytokines in organoid culture increased mitochondrial superoxide twofold, which was completely prevented in aortas isolated from SOD2-K68R mice. These data support the important role of SOD2-K68 acetylation in vascular oxidative stress and pathogenesis of hypertension. We conclude that strategies to reduce SOD2 acetylation may have therapeutic potential in the treatment of vascular dysfunction and hypertension. Essential hypertension is associated with hyperacetylation of key mitochondrial antioxidant SOD2; however, the pathophysiological role of SOD2 acetylation has not been defined. Our animal study of angiotensin II hypertension model shows that deacetylation mimetic SOD2-K68R mutation prevents pathogenic increase in vascular mitochondrial superoxide, abrogates vascular oxidative stress, preserves endothelial nitric oxide, protects endothelial-dependent vasorelaxation, and attenuates hypertension. These data support the important role of SOD2-K68 acetylation in vascular oxidative stress and the pathogenesis of hypertension.
近一半的成年人患有高血压，尽管使用了多种药物，仍有三分之一的患者血压控制不佳，这可能是由于当前治疗方法无法影响到的机制所致。高血压与氧化应激有关；然而，常用的抗氧化剂无效。高血压与关键的内在线粒体抗氧化剂超氧化物歧化酶 2（SOD2）的失活有关，这是由于超乙酰化，但特定的 SOD2 赖氨酸残基的作用尚未确定。高血压与 SOD2 赖氨酸 68 的乙酰化有关，我们假设 SOD2 中的 K68 去乙酰化模拟突变为精氨酸可以抑制血管氧化应激并减轻高血压。为了验证这一假设，我们开发了一种新的 SOD2-K68R 去乙酰化模拟小鼠。我们在 SOD2-K68R 小鼠中进行了血管功能障碍和高血压的血管紧张素 II（ANG II）模型的体内研究。野生型小鼠的 ANG II 输注诱导血管炎症和氧化应激，并将血压升高至 160mmHg。SOD2-K68R 突变完全阻止了线粒体超氧化物的增加，消除了血管氧化应激，维持了内皮一氧化氮的产生，保护了血管舒张，并减轻了 ANG II 诱导的高血压。ANG II 和细胞因子有助于血管氧化应激和高血压。在器官培养中用 ANG II 和细胞因子处理野生型主动脉会使线粒体超氧化物增加两倍，而从 SOD2-K68R 小鼠中分离出的主动脉则完全阻止了这种增加。这些数据支持 SOD2-K68 乙酰化在血管氧化应激和高血压发病机制中的重要作用。我们得出的结论是，降低 SOD2 乙酰化的策略可能具有治疗血管功能障碍和高血压的潜力。原发性高血压与关键线粒体抗氧化剂 SOD2 的过度乙酰化有关；然而，SOD2 乙酰化的病理生理作用尚未确定。我们对血管紧张素 II 高血压模型的动物研究表明，SOD2-K68R 去乙酰化模拟突变可防止血管线粒体超氧化物的致病增加，消除血管氧化应激，维持内皮一氧化氮，保护内皮依赖性血管舒张，并减轻高血压。这些数据支持 SOD2-K68 乙酰化在血管氧化应激和高血压发病机制中的重要作用。
