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 Gq/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 Gq/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 Gq/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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Abe, K., Nakashima, H., Ishida, M. et al. Angiotensin II−Induced Osteopontin Expression in Vascular Smooth Muscle Cells Involves Gq/11, Ras, ERK, Src and Ets-1. Hypertens Res 31, 987–998 (2008). https://doi.org/10.1291/hypres.31.987
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DOI: https://doi.org/10.1291/hypres.31.987
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