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Regulation of Inhibitory Protein-B and Monocyte Chemoattractant Protein-1 by Angiotensin II Type 2 Receptor-Activated Src Homology Protein Tyrosine Phosphatase-1 in Fetal Vascular Smooth Muscle Cells

Department of Medical Biochemistry, Ehime University School of Medicine (L.W., M.I., Z.L., T.S., L.-J.M., T.-X.C., J.-M.L., M.O., M.H.), Shigenobu, Onsen-gun, Ehime 791-0295, Japan; and Centre National de la Recherche Scientifique, UPR0415-Institut Cochin de Genetique Moleculaire (C.N.), Paris, France

Address all correspondence and requests for reprints to: Dr. Masatsugu Horiuchi, Department of Medical Biochemistry, Ehime University School of Medicine, Shigenobu, Onsen-gun, Ehime 791-0295, Japan. E-mail: horiuchi{at}m.ehime-u.ac.jp.

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

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