Activation of extracellular signal-regulated kinases (ERK1/2) by angiotensin II is dependent on c-Src in vascular smooth muscle cells.
Activation of extracellular signal-regulated kinases (ERK1/2) by angiotensin II is dependent on c-Src in vascular smooth muscle cells.
复制标题
DOI：
10.1161/01.res.82.1.7
复制
发表时间：
1998-01
影响因子：
20.1
通讯作者：
M. Ishida;Takafumi Ishida;Sheila M. Thomas;Bradford C. Berk
中科院分区：
文献类型：
--
作者：
M. Ishida;Takafumi Ishida;Sheila M. Thomas;Bradford C. Berk
血管紧张素II （Ang II）介导的信号事件可能对血管平滑肌细胞（VSMCs）很重要，其中包括细胞外信号调节激酶1和2 （ERK1/2）的激活。Ang II激活ERK1/2的上游介质仍然不明确。最近，我们发现Ang II激活了c-Src，一种非受体激酶，它是介导Ang II信号事件的候选激酶。为了确定Ang II激活ERK1/2是否需要c-Src，我们研究了Src家族选择性酪氨酸激酶抑制剂对ERK1/2激活的影响，并研究了Ang II介导的Src缺陷和Src过表达VSMCs的信号事件。酪氨酸激酶抑制剂染料木素和CP-188,556可阻断Ang ii介导的大鼠VSMCs (rVSMCs) ERK1/2活化。我们从c-Src敲除小鼠（Src-/- mVSMCs）的主动脉中获得了Src缺陷的VSMCs。与野生型mVSMCs相比，Src-/- mVSMCs中ERK1/2的基础活性较低，Ang II对ERK1/2的激活显著降低，而ERK1/2蛋白表达和12-肉豆蔻酸13-醋酸酯对ERK1/2的激活相似。为了进一步研究c-Src的作用，我们使用逆转录病毒载体在rVSMCs中过表达野生型或显性阴性c-Src。在过表达c-Src的rVSMCs中，Ang II对ERK1/2的激活显著增加，而在过表达显性阴性c-Src的rVSMCs中，与对照rVSMCs相比，Ang II对ERK1/2的激活显著抑制。这些发现表明，c-Src激活是Ang II刺激VSMCs中ERK1/2所必需的，并表明c-Src在Ang II介导的信号转导中起重要作用。
Among the angiotensin II (Ang II)-mediated signal events likely to be important in vascular smooth muscle cells (VSMCs) is activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). The upstream mediators by which Ang II activates ERK1/2 remain poorly defined. Recently, we showed that Ang II activated c-Src, a nonreceptor kinase, which is a candidate to mediate Ang II signal events. To determine whether c-Src is required for ERK1/2 activation by Ang II, we studied the effects of Src family-selective tyrosine kinase inhibitors on ERK1/2 activation and also studied Ang II-mediated signal events in Src-deficient and Src-overexpressing VSMCs. The tyrosine kinase inhibitors, genistein and CP-188,556, blocked Ang II-mediated ERK1/2 activation in rat VSMCs (rVSMCs). We derived Src-deficient VSMCs from the aortas of c-Src knockout mice (Src-/- mVSMCs). Basal ERK1/2 activity was lower, and activation of ERK1/2 by Ang II was significantly decreased in Src-/- mVSMCs compared with wild-type mVSMCs, whereas ERK1/2 protein expression and ERK1/2 activation by phorbol 12-myristate 13-acetate were similar. To examine the role of c-Src further, we overexpressed wild-type or dominant-negative c-Src in rVSMCs using retroviral vectors. ERK1/2 activation by Ang II was significantly increased in rVSMCs that overexpressed c-Src, whereas ERK1/2 activation by Ang II was significantly inhibited in rVSMCs that overexpressed dominant-negative c-Src compared with control rVSMCs. These findings demonstrate that c-Src activation is required for Ang II stimulation of ERK1/2 in VSMCs and suggest an important role for c-Src in Ang II-mediated signal transduction.