BACKGROUND:Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension.METHODS:To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)–deficient mice using an Ang II (angiotensin II) model of hypertension.RESULTS:Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension.CONCLUSIONS:These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.

中文翻译：

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线粒体 CypD 乙酰化促进内皮功能障碍和高血压

背景：近一半的成年人患有高血压，这是心血管疾病的主要危险因素。线粒体过度乙酰化与高血压有关，但特定蛋白质乙酰化的作用尚不清楚。我们假设线粒体 CypD（亲环蛋白 D）在 K166 处的乙酰化会导致内皮功能障碍和高血压。方法：为了验证这一假设，我们研究了原发性高血压患者的 CypD 乙酰化，确定了 CypD 乙酰化在脱乙酰化模拟 CypD-K166R 中的致病作用突变小鼠和内皮特异性 GCN5L1（氨基酸合成的一般控制 5 像 1）缺陷小鼠使用 Ang II（血管紧张素 II）高血压模型。 结果：高血压患者的小动脉具有 280% 较高的 CypD 乙酰化，同时 Sirt3 降低（ Sirtuin 3) 并增加 GCN5L1 水平。 GCN5L1 调节线粒体蛋白乙酰化并促进 CypD 乙酰化，而线粒体脱乙酰酶 Sirt3 可以抵消这种作用。在人主动脉内皮细胞中，GCN5L1 耗竭可防止超氧化物过度产生。去乙酰化模拟 CypD-K166R 小鼠免受血管氧化应激、内皮功能障碍和 Ang II 诱导的高血压的影响。 Ang II 诱导的高血压增加了线粒体 GCN5L1 并降低了 Sirt3 水平，导致 GCN5L1/Sirt3 比率增加 250%，促进 CypD 乙酰化。使用靶向线粒体的细胞毒性异黄兰素清除剂治疗可使 GCN5L1/Sirt3 比例正常化，减少 CypD 乙酰化并减轻高血压。在内皮特异性 GCN5L1 敲除小鼠中测试了线粒体乙酰转移酶 GCN5L1 在内皮功能中的作用。内皮 GCN5L1 的耗竭可防止 Ang II 诱导的线粒体氧化应激，减少血管代谢向糖酵解的适应不良转换，防止内皮一氧化氮失活，保留内皮依赖性舒张，并减轻高血压。结论：这些数据支持 CypD 的致病作用内皮功能障碍和高血压中的乙酰化。我们建议针对细胞毒性线粒体异黄酮和 GCN5L1 减少 CypD 乙酰化，这可能对心血管疾病有益。