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This version published online on December 18, 2003
Molecular Endocrinology, doi:10.1210/me.2003-0053
Molecular Endocrinology Vol. 0, No. 2003 200300531-
doi:10.1210/me.2003-0053
Copyright © 2003 by the Endocrine Society.
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Submitted on February 19, 2003
Accepted on December 10, 2003

Regulation of I{kappa}B and MCP-1 by Angiotensin Type 2 Receptor-activated SHP-1 in Fetal Vascular Smooth Muscle Cells

Lan Wu1, Masaru Iwai1, Zhen Li1, Tetsuya Shiuchi1, Li-Juan Min1, Tai-Xing Cui1, Jian-Mei Li1, Midori Okumura1, Clara Nahmias1, and Masatsugu Horiuchi1*

1 Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan; CNRS UPR0415-Institut Cochin de Genetique Moleculaire, Paris, France

* To whom correspondence should be addressed. E-mail: horiuchi{at}m.ehime-u.ac.jp.

In the present study, we examined the effects of angiotensin (Ang) II type 2 (AT2) receptor stimulation on AT1 receptor-mediated MCP-1 expression and the possible mechanisms of AT2 receptor-mediated signaling in cultured rat fetal VSMC, which express both AT1 and AT2 receptors. Ang II stimulation induced MCP-1 mRNA expression as well as an increase in NF-{kappa}B binding to the corresponding cis DNA element of the MCP-1 promoter region and a decrease in cytosolic I{kappa}B protein level via AT1 receptor stimulation, whereas, stimulation of the AT2 receptor decreased Ang II-induced MCP-1 expression, NF-{kappa}B DNA binding and I{kappa}B degradation, suggesting that activation of the AT2 receptor attenuated the AT1 receptor-mediated MCP-1 expression via a decrease in NF-{kappa}B DNA binding and increase in I{kappa}B stability. Moreover, we demonstrated that AT2 receptor stimulation attenuated TNF-{alpha}-mediated NF-{kappa}B activation and MCP-1 expression. A tyrosine phosphatase inhibitor, orthovanadate, attenuated the AT2 receptor-mediated increase in I{kappa}B protein level. Moreover, we observed that two I{kappa}B subunits (I{kappa}B{alpha} and I{kappa}B{beta}) were tyrosine phosphorylated after Ang II stimulation. Transfection of a dominant-negative SHP-1 mutant into VSMC inhibited the AT2 receptor-mediated increase in I{kappa}B level, leading to a significant increase in AT1 receptor-induced NF-{kappa}B activation and MCP-1 expression. Taken together, our results demonstrated that AT2 receptor stimulation attenuated MCP-1 expression via I{kappa}B stabilization, and SHP-1 might play a critical role in the transcriptional regulation of MCP-1 expression through the control of I{kappa}B protein stability.
Key words: angiotensin II • MCP-1 • NF-{kappa}B • vascular smooth muscle cell • inflammation




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