Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase.
Angiotensin II impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase.
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DOI：
10.1084/jem.20090449
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发表时间：
2009-12-21
期刊：
影响因子：
--
通讯作者：
Fleming I
中科院分区：
文献类型：
--
作者：
Loot AE;Schreiber JG;Fisslthaler B;Fleming I
富含脯氨酸的酪氨酸激酶2（PYK 2）可被血管紧张素II（Ang II）和活性氧激活。我们报告说，在内皮细胞中，血管紧张素II增强的酪氨酸磷酸化的内皮型一氧化氮合酶（eNOS）在AT 1-，H2 O2-和PYK 2依赖的方式。低浓度（1-100 μmol/L）的H2 O2刺激eNOS Tyr 657的磷酸化，而不影响Ser 1177的磷酸化，并减弱基础和激动剂诱导的NO产生。在离体小鼠睾丸中，30 μmol/L H2 O2诱导Tyr 657上eNOS的磷酸化，并损害乙酰胆碱诱导的舒张。显性负性PYK 2突变体的内皮过表达可保护H2 O2诱导的内皮功能障碍相应地，来自过度表达非磷酸化eNOS Y 657 F突变体的eNOS−/−小鼠的颈动脉也受到了H2 O2的保护。在体内，3周的血管紧张素II治疗显著增加了野生型而非Nox 2 y/−小鼠的血管中Tyr 657磷酸化eNOS的水平，这再次与野生型而非Nox 2 y/−小鼠的内皮依赖性血管舒张功能明显受损相关。总的来说，血管紧张素II和H2 O2激活内皮细胞PYK 2导致eNOS在Tyr 657上的磷酸化，减弱NO的产生和内皮依赖性血管舒张。这一机制可能导致在心血管疾病中观察到的内皮功能障碍，与肾素-血管紧张素系统活性增加和氧化还原应激升高相关。
Proline-rich tyrosine kinase 2 (PYK2) can be activated by angiotensin II (Ang II) and reactive oxygen species. We report that in endothelial cells, Ang II enhances the tyrosine phosphorylation of endothelial NO synthase (eNOS) in an AT1-, H2O2-, and PYK2-dependent manner. Low concentrations (1–100 µmol/liter) of H2O2 stimulated the phosphorylation of eNOS Tyr657 without affecting that of Ser1177, and attenuated basal and agonist-induced NO production. In isolated mouse aortae, 30 µmol/liter H2O2 induced phosphorylation of eNOS on Tyr657 and impaired acetylcholine-induced relaxation. Endothelial overexpression of a dominant-negative PYK2 mutant protected against H2O2-induced endothelial dysfunction. Correspondingly, carotid arteries from eNOS−/− mice overexpressing the nonphosphorylatable eNOS Y657F mutant were also protected against H2O2. In vivo, 3 wk of treatment with Ang II considerably increased levels of Tyr657-phosphorylated eNOS in the aortae of wild-type but not Nox2y/− mice, and this was again associated with a clear impairment in endothelium-dependent vasodilatation in the wild-type but not in the Nox2y/− mice. Collectively, endothelial PYK2 activation by Ang II and H2O2 causes the phosphorylation of eNOS on Tyr657, attenuating NO production and endothelium-dependent vasodilatation. This mechanism may contribute to the endothelial dysfunction observed in cardiovascular diseases associated with increased activity of the renin–angiotensin system and elevated redox stress.
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影响因子：
15.9
作者：
Landmesser, U;Dikalov, S;Harrison, DG
通讯作者：
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作者：
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