Angiotensin II stimulation of NAD(P)H oxidase activity - Upstream mediators
Angiotensin II stimulation of NAD(P)H oxidase activity - Upstream mediators
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DOI：
10.1161/01.res.0000033523.08033.16
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发表时间：
2002-09-06
影响因子：
20.1
通讯作者：
Griendling, KK
中科院分区：
文献类型：
--
作者：
Seshiah, PN;Weber, DS;Griendling, KK
血管紧张素II（Ang II）刺激的血管平滑肌细胞肥大是由NAD（P）H氧化酶衍生的活性氧（ROS）介导的。Ang II激活这些氧化酶的上游信号机制尚不清楚，但可能包括蛋白激酶C、酪氨酸激酶、磷脂酰肌醇-3-激酶和Rac（一种小分子量G蛋白）。我们发现，血管紧张素II刺激的ROS生产是双相的。第一阶段发生迅速（峰值在30秒），并依赖于蛋白激酶C的激活。较大的ROS产生的第二阶段（在30分钟时达到峰值）需要Rac激活，因为艰难梭菌毒素A或显性阴性Rac对Rac的抑制显著抑制了Ang II诱导的ROS产生。磷脂酰肌醇-3-激酶抑制剂（渥曼青霉素或LY 294002）和表皮生长因子（EGF）受体激酶阻断剂AG 1478减弱Rac活化和ROS产生。EGF受体反式激活的上游激活剂c-Src也是ROS产生所需的，因为PPI是一种Src激酶抑制剂，可以消除Ang II对这两种反应的刺激。这些结果表明，c-Src，EGF受体反式激活，磷脂酰肌醇-3-激酶，和Rac在持续的血管紧张素II介导的血管平滑肌细胞NAD（P）H氧化酶的激活中发挥重要作用，并提供了深入了解的综合信号转导机制，从而血管紧张素II刺激导致生长相关的NAD（P）H氧化酶的激活。
Angiotensin II (Ang II)-stimulated hypertrophy of vascular smooth muscle cells is mediated by reactive oxygen species (ROS) derived from NAD(P)H oxidases. The upstream signaling mechanisms by which Ang II activates these oxidases are unclear but may include protein kinase C, tyrosine kinases, phosphatidylinositol-3-kinase, and Rac, a small molecular weight G protein. We found that Ang II-stimulated ROS production is biphasic. The first phase occurs rapidly (peak at 30 seconds) and is dependent on protein kinase C activation. The larger second phase of ROS generation (peak at 30 minutes) requires Rac activation, because inhibition of Rac by either Clostridium difficile toxin A or dominant-negative Rac significantly inhibits Ang II-induced ROS production. Phosphatidylinositol-3-kinase inhibitors (wortmannin or LY294002) and the epidermal growth factor (EGF) receptor kinase blocker AG1478 attenuate both Rac activation and ROS generation. The upstream activator of EGF receptor transactivation, c-Src, is also required for ROS generation, because PPI, an Src kinase inhibitor, abrogates the Ang II stimulation of both responses. These results suggest that c-Src, EGF receptor transactivation, phosphatidylinositol-3-kinase, and Rac play important roles in the sustained Ang II-mediated activation of vascular smooth muscle cell NAD(P)H oxidases and provide insight into the integrated signaling mechanisms whereby Ang II stimulation leads to activation of the growth-related NAD(P)H oxidases.