Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells
Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells
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DOI：
10.1161/01.res.0000180753.63183.95
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发表时间：
2005-09-02
影响因子：
20.1
通讯作者：
Horiuchi, M
中科院分区：
文献类型：
--
作者：
Min, LJ;Mogi, M;Horiuchi, M
醛固酮（Aldo）和血管紧张素II （Ang II）在心血管系统中的相互作用已被强调；然而，其详细的信号机制尚不清楚。在这里，我们研究了血管平滑肌细胞（VSMC）中Aldo和Ang II之间的促生长信号的串扰。较低剂量的Aldo （10(-12) mol/L）和较低剂量的Ang II （10(-10) mol/L）均显著增强了DNA合成，而单独使用Aldo或Ang II对VSMC增殖没有影响。选择性AT(1)受体阻滞剂奥美沙坦、矿皮质激素受体拮抗剂螺内酯、MEK抑制剂PD98059或EGF受体酪氨酸激酶抑制剂AG1478可显著抑制Aldo和Ang II联合作用。Aldo与Ang II联合治疗，即使分别在无效剂量下，也能协同增加细胞外信号调节激酶（ERK）的激活，在10至15分钟和2至4小时达到2个峰值。早期ERK峰可被奥美沙坦或EGF受体激酶抑制剂AG1478有效阻断，但不被螺内酯阻断，而晚期ERK峰可被奥美沙坦和螺内酯完全抑制。Aldo和Ang II联合治疗降低了丝裂原活化蛋白激酶磷酸酶-1 （MKP-1）的表达，增加了Ki-ras2A的表达。Ki-ras2A-siRNA处理的VSMC未观察到晚期ERK峰。有趣的是，PD98059或AG1478恢复了MKP-1表达的下降和Ki-ras2A表达的增加。这些结果表明Aldo与Ang II具有协同有丝分裂作用，并支持Aldo和Ang II的阻断可以更有效地阻止血管重构的观点。
Interaction between aldosterone ( Aldo) and angiotensin II ( Ang II) in the cardiovascular system has been highlighted; however, its detailed signaling mechanism is poorly understood. Here, we examined the cross-talk of growth-promoting signaling between Aldo and Ang II in vascular smooth muscle cells (VSMC). Treatment with a lower dose of Aldo (10(-12) mol/L) and with a lower dose of Ang II (10(-10) mol/ L) significantly enhanced DNA synthesis, whereas Aldo or Ang II alone at these doses did not affect VSMC proliferation. This effect of a combination of Aldo and Ang II was markedly inhibited by a selective AT(1) receptor blocker, olmesartan, a mineralocorticoid receptor antagonist, spironolactone, an MEK inhibitor, PD98059, or an EGF receptor tyrosine kinase inhibitor, AG1478. Treatment with Aldo together with Ang II, even at noneffective doses, respectively, synergistically increased extracellular signal-regulated kinase (ERK) activation, reaching 2 peaks at 10 to 15 minutes and 2 to 4 hours. The early ERK peak was effectively blocked by olmesartan or an EGF receptor kinase inhibitor, AG1478, but not by spironolactone, whereas the late ERK peak was completely inhibited by not only olmesartan, but also spironolactone. Combined treatment with Aldo and Ang II attenuated mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and increased Ki-ras2A expression. The late ERK peak was not observed in VSMC treated with Ki-ras2A-siRNA. Interestingly, the decrease in MKP-1 expression and the increase in Ki-ras2A expression were restored by PD98059 or AG1478. These results suggest that Aldo exerts a synergistic mitogenic effect with Ang II and support the notion that blockade of both Aldo and Ang II could be more effective to prevent vascular remodeling.