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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2879    most recent 91406.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Takahashi, M. Articles by Hirata, Y. PubMed PubMed Citation Articles by Takahashi, M. Articles by Hirata, Y.

Angiotensin II and tumor necrosis factor- synergistically promote monocyte chemoattractant protein-1 expression: roles of NF-B, p38, and reactive oxygen species

¹Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo; ²Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki; and ³Department of Urology, Faculty of Medicine, and ⁴Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Submitted 6 December 2007 ; accepted in final form 23 April 2008

We examined whether ANG II and TNF- cooperatively induce vascular inflammation using the expression of monocyte chemoattractant protein (MCP)-1 as a marker of vascular inflammation. ANG II and TNF- stimulated MCP-1 expression in a synergistic manner in vascular smooth muscle cells. ANG II-induced MCP-1 expression was potently inhibited to a nonstimulated basal level by blockade of the p38-dependent pathway but only partially inhibited by blockade of the NF-B-dependent pathway. In contrast, TNF--induced MCP-1 expression was potently suppressed by blockade of NF-B activation but only modestly suppressed by blockade of p38 activation. ANG II- and TNF--induced activation of NF-B- and p38-dependent pathways was partially inhibited by pharmacological inhibitors of ROS production. Furthermore, ANG II- and TNF--stimulated MCP-1 expression was partially suppressed by ROS inhibitors. We also examined whether endogenous ANG II and TNF- cooperatively promote vascular inflammation in vivo using a wire injury model of the rat femoral artery. Blockade of both ANG II and TNF- further suppressed neointimal formation, macrophage infiltration, and MCP-1 expression in an additive manner compared with blockade of ANG II or TNF- alone. These results suggested that ANG II and TNF- synergistically stimulate MCP-1 expression via the utilization of distinct intracellular signaling pathways (p38- and NFB-dependent pathways) and that these pathways are activated in ROS-dependent and -independent manners. These results also suggest that ANG II and TNF- cooperatively stimulate vascular inflammation in vivo as well as in vitro.

blood vessels; signaling pathway; atherosclerosis