Angiotensin II-Induced osteopontin expression in vascular smooth muscle cells involves Gq/11, Ras, ERK, Src and Ets-1
Angiotensin II-Induced osteopontin expression in vascular smooth muscle cells involves Gq/11, Ras, ERK, Src and Ets-1
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DOI：
10.1291/hypres.31.987
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发表时间：
2008-05-01
影响因子：
5.4
通讯作者：
Ishida, Takafumi
中科院分区：
文献类型：
--
作者：
Abe, Keiko;Nakashima, Hidekatsu;Ishida, Takafumi
最近的研究表明，骨桥蛋白（OPN）在动脉粥样硬化斑块的进展中起着关键作用，血管紧张素II（Ang II）是OPN表达的有效上调剂。本研究的目的是表征血管紧张素II增加血管平滑肌细胞（VSMC）中OPN表达的信号转导机制。G（q/11）的特异性抑制剂YM-254890有效地抑制Ang [1]诱导的OPN表达和ERK 1/2活化。在小G蛋白的显性阴性（DN）突变体中，只有DN-Ras抑制Ang II诱导的OPN启动子活性。DN-MEK 1显著抑制Ang II诱导的OPN启动子活性，而DN-JNK和DN-p38 MAP激酶均无任何作用。DN-Src和DN-Fyn抑制Ang II诱导的OPN启动子活性。YM-254890抑制Ang II诱导的Src和Ras激活，而Src激酶家族的选择性抑制剂PP 2抑制Ras激活，表明G（q/11）-Src-Ras轴是Ang II诱导的OPN表达的上游信号级联。最后，针对Ets-1的小干扰RNA抑制Ang II诱导的OPN表达。总之，这些数据表明，血管紧张素II诱导的OPN表达在VSMC是介导的信号级联涉及G（q/11），RasERK轴，Src激酶家族，并通过转录因子，Ets-1。这些信号分子可能是预防病理性血管重塑的治疗靶点。
Recent studies suggest that osteopontin (OPN) plays a critical role in the progression of atherosclerotic plaques and that angiotensin II (Ang II) is a potent upregulator of OPN expression. The goal of the present study was to characterize the signaling mechanisms whereby Ang II increases OPN expression in vascular smooth muscle cells (VSMC). YM-254890, a specific inhibitor of G(q/11) potently suppressed Ang [I-induced OPN expression and ERK1/2 activation. Among dominant-negative (DN) mutants of small G proteins, only DN-Ras suppressed Ang II-induced OPN promoter activity. DN-MEK1 markedly inhibited Ang II-induced OPN promoter activity, while neither DN-JNK nor DN-p38 MAP kinase had any effect. DN-Src and DN-Fyn suppressed Ang II-induced OPN promoter activity. YM-254890 inhibited Ang II-induced Src and Ras activation, and PP2, a selective inhibitor for the Src kinase family, inhibited Ras activation, suggesting that the G(q/11)-Src-Ras axis is the upstream signaling cascade for Ang II-induced OPN expression. Finally, small interfering RNA against Ets-1 suppressed Ang II-induced OPN expression. In conclusion, these data suggest that Ang II-induced OPN expression in VSMC is mediated by signaling cascades involving G(q/11) , the RasERK axis, and the Src kinase family, and by the transcription factor, Ets-1. These signaling molecules may represent therapeutic targets for the prevention of pathological vascular remodeling.