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  • Title: Angiotensin II-induced osteopontin expression in vascular smooth muscle cells involves Gq/11, Ras, ERK, Src and Ets-1.
    Author: Abe K, Nakashima H, Ishida M, Miho N, Sawano M, Soe NN, Kurabayashi M, Chayama K, Yoshizumi M, Ishida T.
    Journal: Hypertens Res; 2008 May; 31(5):987-98. PubMed ID: 18712054.
    Abstract:
    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 II-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 Ras-ERK 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.
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