NADPH Oxidase Mediates Tissue Factor–Dependent Surface Procoagulant Activity by Thrombin in Human Vascular Smooth Muscle Cells

• DOI: 10.1161/01.cir.0000014611.28864.1e
• Publication Date: 2002-07-28T23:16:47Z
• Authors: Olaf Herkert; Isabel Diebold; Ralf P. Brandes; John Hess; Rudi Busse; Agnes Görlach
• Keywords: P22phox

Tissue factor (TF) initiates the extrinsic coagulation cascade leading to thrombin formation. Thrombin induces TF mRNA in vascular smooth muscle cells (VSMCs), thereby contributing prolonged procoagulant activity and enhanced thrombogenicity at sites of injury. However, signaling mechanisms mediating this thrombogenic cycle are unclear. Characteristically, injury promotes generation reactive oxygen species (ROS). Because ROS exert functions, we investigated whether NADPH oxidase, an important source VSMCs, contributes upregulation by thrombin.Thrombin not only stimulated expression, but also TF-dependent surface cultured human VSMCs. This response was attenuated antioxidants; flavin inhibitor diphenylene-iodonium, Clostridium difficile toxin B, which inhibits Rho GTPases, p22phox antisense oligonucleotides, or dominant-negative RacT17N mutant. Inhibitors p38 MAP kinase phosphatidylinositol (PI) 3-kinase prevented thrombin-stimulated expression. Furthermore, phosphorylation PI target protein B/Akt a redox-sensitive oxidase-dependent manner.These findings indicate that oxidase is essentially involved induction expression thrombin. mediated activation 3-kinase/protein pathway. Given active formation, may play crucial role perpetuating injured vessel wall.