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-induced MCP-1 Gene Expression in Endothelial Cells: Role of Rac1 and NADPH Oxidase
1 Discovery Research, AtheroGenics, Inc., Alpharetta, GA, USA; Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
2 Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: xchen{at}atherogenics.com.
Reactive oxygen species (ROS) play an important, but not fully defined role in the expression of inflammatory genes such as monocyte chemoattractant protein-1 (MCP-1). We utilized complementary molecular and biochemical approaches to explore the roles of specific ROS and their molecular linkage to inflammatory signaling in endothelial cells. A denoviral mediated expression of superoxide dismutase and catalase inhibited TNF-
-induced MCP-1 gene expression, suggesting important roles of superoxide (O2-.) and H2O2 in the MCP-1 gene activation. In addition, the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one and hydroxyl radical scavengers dimethylthiourea and dimethyl sulfoxide inhibited TNF--induced MCP-1 expression, suggesting important roles of iron and hydroxyl radicals in inflammatory signal activation. In contrast, scavenging of peroxynitrite with FeTPPS had no effect on TNF-- induced MCP-1 expression. Inhibition of NADPH oxidase, a major oxidase responsible for O2-. generation, with diphenylene iodonium suppressed TNF--induced MCP-1 mRNA accumulation. Rac1 is an upstream signal for the activation of NADPH oxidase and O2-. generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF--induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-- induced MCP-1 and NF-
B transcriptional activity. These data suggest that ROS such as superoxide, H2O2 derived from Rac1 activated NADPH oxidase mediate TNF--induced MCP-1 expression in endothelial cells.
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