TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension
TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension
复制标题
TMEM16A 通过促进高血压中 Nox2 NADPH 氧化酶衍生的活性氧生成而导致内皮功能障碍
DOI：
10.1161/hypertensionaha.116.08874
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发表时间：
2017-05-01
期刊：
影响因子：
8.3
通讯作者：
Guan, Yong-Yuan
中科院分区：
文献类型：
--
作者：
Ma, Ming-Ming;Gao, Min;Guan, Yong-Yuan
Ca ~（2+）激活的Cl ~-通道在多种生理过程中起着重要作用。然而，TMEM 16 A在高血压期间血管内皮功能障碍中的作用尚不清楚。在这项研究中，我们研究了TMEM 16 A在调节内皮功能和血压中的具体参与及其潜在机制。逆转录聚合酶链反应，蛋白质印迹，共免疫沉淀，共聚焦成像，膜片钳记录，和TMEM 16 A内皮特异性转基因和敲除小鼠。我们发现TMEM 16 A在内皮细胞中大量表达，并作为Ca 2+激活的Cl-通道发挥作用。血管紧张素II诱导内皮功能障碍，TMEM 16 A表达增加。敲除内皮特异性TMEM 16 A可显著降低血管紧张素II诱导的高血压患者的血压并改善内皮功能障碍，而过度表达内皮特异性TMEM 16 A则产生相反的效果。这些结果与TMEM 16 A促进血管紧张素II诱导的高血压激发后活性氧产生增加、含Nox 2的NADPH氧化酶活化以及Nox 2和p22 phox蛋白表达有关。TMEM 16 A与Nox 2直接结合，通过蛋白酶体依赖性降解途径减少Nox 2的降解。因此，TMEM 16 A是通过含Nox 2的NADPH氧化酶产生内皮活性氧的正调节剂，其诱导内皮功能障碍和高血压。TMEM 16 A的修饰可能是内皮功能障碍相关疾病的新治疗策略。
Ca2+-activated Cl-channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism. Reverse transcription-polymerase chain reaction, Western blotting, coimmunoprecipitation, confocal imaging, patch-clamp recordings, and TMEM16A endothelial-specific transgenic and knockout mice were used. We found that TMEM16A was expressed abundantly and functioned as a Ca2+-activated Cl-channel in endothelial cells. Angiotensin II induced endothelial dysfunction with an increase in TMEM16A expression. The knockout of endothelial-specific TMEM16A significantly lowered the blood pressure and ameliorated endothelial dysfunction in angiotensin II-induced hypertension, whereas the overexpression of endothelial-specific TMEM16A resulted in the opposite effects. These results were related to the increased reactive oxygen species production, Nox2-containing NADPH oxidase activation, and Nox2 and p22phox protein expression that were facilitated by TMEM16A on angiotensin II-induced hypertensive challenge. Moreover, TMEM16A directly bound with Nox2 and reduced the degradation of Nox2 through the proteasome-dependent degradation pathway. Therefore, TMEM16A is a positive regulator of endothelial reactive oxygen species generation via Nox2-containing NADPH oxidase, which induces endothelial dysfunction and hypertension. Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated diseases.