Thrombin-induced MCP-1 expression involves activation of the p22phox-containing NADPH oxidase in human vascular smooth muscle cells

Activation of vascular smooth muscle cells (VMSC) by thrombin induces the e xpression of the chemokine. monocyte chemoattractant protein-1 (MCP-1). We investigated in cultured human and rat VSMC whether reactive oxygen species (ROS) derived from the vascular NADPH oxidase contribute to this effect. E xposure of cultured VSMC To thrombin rapidly increased ROS formation, phosp horylation of p38 MAP kinase as well as the expression of MCP-1. Specific i nhibition of the p22phox subunit of the vascular NADPH oxidase using either p22phox neutralizing antibody or p22phox antisense oligonucleotides attenu ated thrombin-induced ROS generation. Furthermore, thrombin-induced p38 MAP kinase activation as well as MCP-1 expression were impaired by antioxidant s as well as by p22phox antisense oligonucleotides. Inhibition of p38 MAP k inase diminished the thrombin-induced expression of MCP-1. Conclusion: Thro mbin, by activating a p22phox-containing NADPH oxidase. elicits ROS generat ion and activation of p38 MAP kinase in VSMC. The subsequent induction of M CP-I expression highligts the crucial role of the p22phox-containing NADPH oxidase in thrombin-induced signal transduction in VSMC.