Role of insulin-like growth factor 1 receptor and c-Src in endothelin-1-and angiotensin II-induced PKB phosphorylation, and hypertrophic and proliferative responses in vascular smooth muscle cells
Role of insulin-like growth factor 1 receptor and c-Src in endothelin-1-and angiotensin II-induced PKB phosphorylation, and hypertrophic and proliferative responses in vascular smooth muscle cells
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DOI：
10.1139/y09-056
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发表时间：
2009-12-01
影响因子：
2.1
通讯作者：
Srivastava, Ashok K.
中科院分区：
文献类型：
--
作者：
Bouallegue, Ali;Vardatsikos, George;Srivastava, Ashok K.
内皮素-1(ET-1)和血管紧张素II(Ang II)是血管活性多肽，被认为与高血压、动脉粥样硬化、肥厚和再狭窄等血管异常的发病机制有关。在过去的几年里，生长因子受体，如表皮生长因子受体(EGFR)，在触发血管活性多肽诱导的信号事件中的反式激活的概念得到了越来越多的认可。我们已经证明，胰岛素样生长因子1型受体(IGF-1R)在转导H_2O_2的作用，导致蛋白激酶B(PKB)磷酸化。由于血管活性多肽通过产生包括H_2O_2在内的活性氧物种来诱导其反应，我们研究了IGF-1R反式激活在ET-1和Ang II诱导的血管平滑肌细胞(VSMC)的PKB磷酸化和肥大反应中是否起到类似的作用。IGF1R蛋白酪氨酸激酶(PTK)的特异性抑制剂AG1024以剂量依赖的方式减弱ET-1和Ang II诱导的PKB磷酸化。ET-1和Ang II还可诱导IGF-1R自磷酸化位点酪氨酸残基的磷酸化，该作用可被AG1024阻断。此外，ET-1和Ang II均可诱导非受体PTK c-Src的酪氨酸磷酸化，而药物抑制c-Src PTK活性可显著降低这两种血管活性多肽诱导的PKB磷酸化和IGF-1R的酪氨酸磷酸化。此外，AG1024和PP2可减弱ET-1和Ang II促进的蛋白质和DNA合成。综上所述，这些结果提示IGF-1R PTK和c-Src PTK在介导PKB磷酸化以及ET-1和Ang II诱导的A10 VSMC肥大和增殖反应中起重要作用。
Endothelin-1 (ET-1) and angiotensin II (Ang II) are vasoactive peptides believed to contribute to the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy, and restenosis. The concept of transactivation of growth factor receptors, such as epidermal growth factor receptor (EGFR), in triggering vasoactive peptide-induced signaling events has gained much recognition during the past several years. We have demonstrated that insulin-like growth factor type 1 receptor (IGF-1R) plays a role in transducing the effect of H2O2, leading to protein kinase B (PKB) phosphorylation. Since vasoactive peptides elicit their responses through generation of reactive oxygen species, including H2O2, we investigated whether IGF-1R transactivation plays a similar role in ET-1- and Ang II-induced PKB phosphorylation and hypertrophic responses in vascular smooth muscle cells (VSMC). AG1024, a specific inhibitor of IGF-1R protein tyrosine kinase (PTK), attenuated both ET-1- and Ang II-induced PKB phosphorylation in a dose-dependent manner. ET-1 and Ang II treatment also induced the phosphorylation of tyrosine residues in the autophosphorylation sites of IGF-1R, which were blocked by AG1024. In addition, both ET-1 and Ang II evoked tyrosine phosphorylation of c-Src, a nonreceptor PTK, whereas pharmacological inhibition of c-Src PTK activity by PP2, a specific inhibitor of Src-family tyrosine kinase, significantly reduced PKB phosphorylation as well as tyrosine phosphorylation of IGF-1R induced by the 2 vasoactive peptides. Furthermore, protein and DNA synthesis enhanced by ET-1 and Ang II were attenuated by AG1024 and PP2. In conclusion, these data suggest that IGF-1R PTK and c-Src PTK play a critical role in mediating PKB phosphorylation as well as hypertrophic and proliferative responses induced by ET-1 and Ang II in A10 VSMC.