Journal
MOLECULAR ENDOCRINOLOGY
Volume 18, Issue 3, Pages 666-678Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2003-0053
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In the present study we examined the effects of angiotensin II (Ang II) type 2 (AT 2) receptor stimulation on AT 1 receptor-mediated monocyte chemoattractant protein-1 (MCP-1) expression and the possible mechanisms of AT 2 receptor-mediated signaling in cultured rat fetal vascular smooth muscle cells, which express both AT 1 and AT 2 receptors. Ang II stimulation induced MCP-1 mRNA expression as well as an increase in nuclear factor-kappaB (NF-kappaB) binding to the corresponding cis DNA element of the MCP-1 promoter region and a decrease in the cytosolic inhibitory protein-kappaB (IkappaB)protein level via AT 1 receptor stimulation, whereas stimulation of the AT 2 receptor decreased Ang II-induced MCP-1 expression, NF-kappaB DNA binding, and IkappaB degradation, suggesting that activation of the AT 2 receptor attenuated AT 1 receptor-mediated MCP-1 expression via a decrease in NF-kappaB DNA binding and an increase in IkappaB stability. Moreover, we demonstrated that AT(2) receptor stimulation attenuated TNFalpha-mediated NF-kappaB activation and MCP-1 expression. A tyrosine phosphatase inhibitor, orthovanadate, attenuated the AT(2) receptor-mediated increase in IkappaB protein. Moreover, we observed that two IkappaB subunits (IkappaBalpha and IkappaBalpha)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 AT(2) receptor-mediated increase in IkappaB, leading to a significant increase in AT 1 receptor-induced NF-kappaB activation and MCP-1 expression. Taken together, our results demonstrated that AT(2) receptor stimulation attenuated MCP-1 expression via IkappaB 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 IkappaB protein stability.
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