RGD Reference Report - Regulation of inhibitory protein-kappaB and monocyte chemoattractant protein-1 by angiotensin II type 2 receptor-activated Src homology protein tyrosine phosphatase-1 in fetal vascular smooth muscle cells. - Rat Genome Database

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Regulation of inhibitory protein-kappaB and monocyte chemoattractant protein-1 by angiotensin II type 2 receptor-activated Src homology protein tyrosine phosphatase-1 in fetal vascular smooth muscle cells.

Authors: Wu, L  Iwai, M  Li, Z  Shiuchi, T  Min, LJ  Cui, TX  Li, JM  Okumura, M  Nahmias, C  Horiuchi, M 
Citation: Wu L, etal., Mol Endocrinol. 2004 Mar;18(3):666-78. Epub 2003 Dec 18.
RGD ID: 1582323
Pubmed: (View Article at PubMed) PMID:14684844
DOI: Full-text: DOI:10.1210/me.2003-0053

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 IkappaBbeta) 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.



Molecular Pathway Annotations    
Objects Annotated

Genes (Rattus norvegicus)
Ccl2  (C-C motif chemokine ligand 2)

Genes (Mus musculus)
Ccl2  (chemokine (C-C motif) ligand 2)

Genes (Homo sapiens)
CCL2  (C-C motif chemokine ligand 2)


Additional Information