Department of Biological Sciences, Kent State University, OH 44242, USA.
Arch Biochem Biophys. 2010 Jun 1;498(1):50-6. doi: 10.1016/j.abb.2010.04.003. Epub 2010 Apr 11.
Angiotensin (Ang) II stimulates vascular smooth muscle cell (VSMC) growth via activation of cytosolic phospholipase A(2) (cPLA(2)), release of arachidonic acid (ArAc) and activation of mitogen-activated protein kinase (MAPK). The mechanism linking AT(1) receptor stimulation of ArAc release with MAPK activation may involve transactivation of the epidermal growth factor receptor (EGFR). In this study, Ang II increased phosphorylation of the EGFR and MAPK in cultured VSMC and these effects were attenuated by the cPLA(2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF(3)), and restored by addition of ArAc. Ang II- or ArAc-induced phosphorylation of the EGFR and MAPK were abolished by the EGFR kinase inhibitor AG1478. Ang II or ArAc also stimulated VSMC growth that was blocked by AG1478 or the MAPK kinase (MEK) inhibitor PD98059. Thus, it appears that the cPLA(2)-dependent release of ArAc may provide a mechanism for the transactivation between the AT(1) receptor and the EGFR signaling cascade.
血管紧张素 II（Ang II）通过激活细胞质磷脂酶 A2（cPLA2）、释放花生四烯酸（ArAc）和激活丝裂原活化蛋白激酶（MAPK）来刺激血管平滑肌细胞（VSMC）生长。将 AT1 受体刺激 ArAc 释放与 MAPK 激活联系起来的机制可能涉及表皮生长因子受体（EGFR）的转激活。在这项研究中，Ang II 增加了培养的 VSMC 中 EGFR 和 MAPK 的磷酸化，这些作用被 cPLA2 抑制剂花生四烯酸三氟甲基酮（AACOCF3）减弱，并通过添加 ArAc 恢复。EGFR 激酶抑制剂 AG1478 可消除 Ang II 或 ArAc 诱导的 EGFR 和 MAPK 的磷酸化。Ang II 或 ArAc 还刺激 VSMC 生长，该生长被 AG1478 或 MAPK 激酶（MEK）抑制剂 PD98059 阻断。因此，看来 cPLA2 依赖性 ArAc 释放可能为 AT1 受体和 EGFR 信号级联之间的转激活提供了一种机制。
