From the Vanderbilt University Medical Center, Nashville, TN (A.D., L.X., V.A., I.Z.-I., A.V., M.A., V.Y., R.R.N., O.B., M.G.L., F.T.B., S. Davies, L.J.R., D.G.H., S. Dikalov).
Mercer University School of Medicine, Macon, Georgia (V.M.).
Hypertension. 2020 Dec;76(6):1980-1991. doi: 10.1161/HYPERTENSIONAHA.120.15236. Epub 2020 Oct 5.
Hypertension remains a major health problem in Western Societies, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs. Mitochondrial dysfunction contributes to hypertension, and mitochondria-targeted agents can potentially improve treatment of hypertension. We have proposed that mitochondrial oxidative stress produces reactive dicarbonyl lipid peroxidation products, isolevuglandins, and that scavenging of mitochondrial isolevuglandins improves vascular function and reduces hypertension. To test this hypothesis, we have studied the accumulation of mitochondrial isolevuglandins-protein adducts in patients with essential hypertension and Ang II (angiotensin II) model of hypertension using mass spectrometry and Western blot analysis. The therapeutic potential of targeting mitochondrial isolevuglandins was tested by the novel mitochondria-targeted isolevuglandin scavenger, mito2HOBA. Mitochondrial isolevuglandins in arterioles from hypertensive patients were 250% greater than in arterioles from normotensive subjects, and ex vivo mito2HOBA treatment of arterioles from hypertensive subjects increased deacetylation of a key mitochondrial antioxidant, SOD2 (superoxide dismutase 2). In human aortic endothelial cells stimulated with Ang II plus TNF (tumor necrosis factor)-α, mito2HOBA reduced mitochondrial superoxide and cardiolipin oxidation, a specific marker of mitochondrial oxidative stress. In Ang II-infused mice, mito2HOBA diminished mitochondrial isolevuglandins-protein adducts, raised Sirt3 (sirtuin 3) mitochondrial deacetylase activity, reduced vascular superoxide, increased endothelial nitric oxide, improved endothelium-dependent relaxation, and attenuated hypertension. Mito2HOBA preserved mitochondrial respiration, protected ATP production, and reduced mitochondrial permeability pore opening in Ang II-infused mice. These data support the role of mitochondrial isolevuglandins in endothelial dysfunction and hypertension. We conclude that scavenging of mitochondrial isolevuglandins may have therapeutic potential in treatment of vascular dysfunction and hypertension.
高血压仍然是西方社会的一个主要健康问题，尽管使用了多种药物，仍有三分之一的患者血压控制不佳。线粒体功能障碍与高血压有关，靶向线粒体的药物可能改善高血压的治疗效果。我们提出，线粒体氧化应激产生活性二羰基脂质过氧化产物异戊二醛，清除线粒体异戊二醛可改善血管功能并降低高血压。为了验证这一假说，我们使用质谱和 Western blot 分析研究了原发性高血压患者和 Ang II（血管紧张素 II）高血压模型中线粒体异戊二醛蛋白加合物的积累。通过新型线粒体靶向异戊二醛清除剂 mito2HOBA 测试了靶向线粒体异戊二醛的治疗潜力。高血压患者小动脉中的线粒体异戊二醛比正常血压受试者的小动脉高 250%，而 mito2HOBA 对高血压受试者小动脉的离体处理增加了关键线粒体抗氧化剂 SOD2（超氧化物歧化酶 2）的去乙酰化。在 Ang II 加 TNF（肿瘤坏死因子）-α刺激的人主动脉内皮细胞中，mito2HOBA 减少了线粒体超氧化物和心磷脂氧化，这是线粒体氧化应激的一个特定标志物。在 Ang II 输注小鼠中，mito2HOBA 减少了线粒体异戊二醛蛋白加合物，提高了 Sirt3（沉默调节蛋白 3）线粒体去乙酰化酶活性，减少了血管内超氧化物，增加了内皮一氧化氮，改善了内皮依赖性松弛，并减轻了高血压。Mito2HOBA 保留了线粒体呼吸，保护了 Ang II 输注小鼠的 ATP 产生，并减少了线粒体通透性孔的开放。这些数据支持线粒体异戊二醛在血管内皮功能障碍和高血压中的作用。我们得出结论，清除线粒体异戊二醛可能具有治疗血管功能障碍和高血压的潜力。
