The GTPase ARF6 Controls ROS Production to Mediate Angiotensin II-Induced Vascular Smooth Muscle Cell Proliferation.
The GTPase ARF6 Controls ROS Production to Mediate Angiotensin II-Induced Vascular Smooth Muscle Cell Proliferation.
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DOI：
10.1371/journal.pone.0148097
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Claing A
中科院分区：
文献类型：
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作者：
Bourmoum M;Charles R;Claing A
在许多心血管疾病中观察到高活性氧簇(ROS)水平和促进血管平滑肌细胞(VSMC)的增殖。血管紧张素II(Ang II)等激素促进这些细胞反应的机制仍然知之甚少。我们先前已经证明，ADP核糖化因子6(ARF6)，一个协调细胞内信号事件的分子开关，可以被Ang II受体(AT1R)激活。然而，这种小的GTP结合蛋白是否控制导致ROS产生的信号事件，从而导致Ang II依赖的VSMC增殖，仍是未知的。在这里，我们证明了在大鼠主动脉VSMC中，Ang II刺激导致了随后的ARF6和rac1的激活，这是NADPH氧化酶活性的关键调节因子。利用RNA干扰，我们证明了ARF6对于ROS的产生是必不可少的，因为在GTP酶被击倒的条件下，Ang II不再能促进超氧阴离子的产生。除了调节rac1的活性外，ARF6还控制NADPH氧化酶1(Nox 1)的表达以及EGFR反式激活的能力。最后，ARF6还控制MAPK(ERK1/2、p38和JNK)的激活，MAPK是VSMC增殖的关键途径。综上所述，我们的发现表明，Ang II通过调节rac1的激活和Nox1的表达来促进ARF6的激活，从而控制ROS的产生。反过来，增加的ROS作用于激活MAPK通路。这些信号事件代表了Ang II促进VSMC增殖的新的分子机制。
High reactive oxygen species (ROS) levels and enhanced vascular smooth muscle cells (VSMC) proliferation are observed in numerous cardiovascular diseases. The mechanisms by which hormones such as angiotensin II (Ang II) acts to promote these cellular responses remain poorly understood. We have previously shown that the ADP-ribosylation factor 6 (ARF6), a molecular switch that coordinates intracellular signaling events can be activated by the Ang II receptor (AT1R). Whether this small GTP-binding protein controls the signaling events leading to ROS production and therefore Ang II-dependent VSMC proliferation, remains however unknown. Here, we demonstrate that in rat aortic VSMC, Ang II stimulation led to the subsequent activation of ARF6 and Rac1, a key regulator of NADPH oxidase activity. Using RNA interference, we showed that ARF6 is essential for ROS generation since in conditions where this GTPase was knocked down, Ang II could no longer promote superoxide anion production. In addition to regulating Rac1 activity, ARF6 also controlled expression of the NADPH oxidase 1 (Nox 1) as well as the ability of the EGFR to become transactivated. Finally, ARF6 also controlled MAPK (Erk1/2, p38 and Jnk) activation, a key pathway of VSMC proliferation. Altogether, our findings demonstrate that Ang II promotes activation of ARF6 to controls ROS production by regulating Rac1 activation and Nox1 expression. In turn, increased ROS acts to activate the MAPK pathway. These signaling events represent a new molecular mechanism by which Ang II can promote proliferation of VSMC.