Department of Physiology, Faculty of Medicine, University of Montreal, Montréal, Québec, Canada.
Am J Physiol Heart Circ Physiol. 2010 Dec;299(6):H1959-67. doi: 10.1152/ajpheart.00526.2010. Epub 2010 Sep 17.
We showed previously that vascular smooth muscle cells (VMSC) from spontaneously hypertensive rats (SHR) exhibit increased proliferation. The present study was undertaken to examine whether the enhanced levels of endogenous angiotensin (ANG) II and endothelin (ET)-1 contribute to the enhanced proliferation of VSMC from SHR and to further investigate the underlying mechanisms responsible for this response. The enhanced proliferation of VSMC from SHR compared with Wistar-Kyoto (WKY) rats was attenuated by losartan, BQ-123, BQ-788, and AG-1478, inhibitors of AT(1), ET(A), ET(B) and epidermal growth factor (EGF-R) receptors, respectively. In addition, BQ-123 and BQ-788 also attenuated the enhanced production of superoxide anion (O(2)(-)) and NADPH oxidase activity. Furthermore, diphenyleneiodonium (DPI, inhibitor of NADPH oxidase), N-acetyl-L-cysteine (NAC, O(2)(-) scavenger), and PP2 (inhibitor of c-Src) also inhibited the augmented proliferation of VSMC from SHR to WKY levels. In addition, the enhanced phosphorylation of EGF-R in VSMC from SHR compared with WKY was also attenuated by inhibitors of AT(1), ET(A), ET(B), and EGF-R but not by inhibitors of platelet-derived growth factor receptor or insulin-like growth factor receptor. Furthermore, the enhanced phosphorylation of ERK1/2 in VSMC from SHR was also attenuated by AT(1), ET(A), ET(B), c-Src, and EGF-R inhibitors. The phosphorylation of c-Src was significantly augmented in VSMC from SHR compared with VSMC from WKY and was attenuated by DPI and NAC. These data suggest that endogenous vasoactive peptides, through increased oxidative stress and resultant activation of c-Src, transactivate EGF-R, which through mitogen-activated protein (MAP) kinase signaling may contribute to the hyperproliferation of VSMC from SHR.
我们之前已经表明，自发性高血压大鼠（SHR）的血管平滑肌细胞（VSMC）表现出增殖增加。本研究旨在检查增强的内源性血管紧张素（ANG）II 和内皮素（ET）-1 水平是否导致 SHR 的 VSMC 增殖增强，并进一步研究导致这种反应的潜在机制。与 Wistar-Kyoto（WKY）大鼠相比，SHR 的 VSMC 增殖增强被 losartan、BQ-123、BQ-788 和 AG-1478 减弱，它们分别是 AT（1）、ET（A）、ET（B）和表皮生长因子（EGF-R）受体的抑制剂。此外，BQ-123 和 BQ-788 还减弱了超氧阴离子（O（2）（-））和 NADPH 氧化酶活性的增强产生。此外，二苯并碘（DPI，NADPH 氧化酶抑制剂）、N-乙酰-L-半胱氨酸（NAC，O（2）（-）清除剂）和 PP2（c-Src 抑制剂）也抑制了 SHR 的 VSMC 增殖到 WKY 水平。此外，与 WKY 相比，SHR 的 VSMC 中 EGF-R 的磷酸化增强也被 AT（1）、ET（A）、ET（B）和 EGF-R 的抑制剂减弱，但不被血小板衍生生长因子受体或胰岛素样生长因子受体的抑制剂减弱。此外，SHR 的 VSMC 中 ERK1/2 的磷酸化也被 AT（1）、ET（A）、ET（B）、c-Src 和 EGF-R 抑制剂减弱。与 WKY 的 VSMC 相比，SHR 的 VSMC 中的 c-Src 磷酸化明显增强，并且被 DPI 和 NAC 减弱。这些数据表明，内源性血管活性肽通过增加氧化应激和由此导致的 c-Src 激活，转激活 EGF-R，通过丝裂原激活蛋白（MAP）激酶信号可能有助于 SHR 的 VSMC 过度增殖。
