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NADPH oxidase mediates tissue factor-dependent surface procoagulant activity by thrombin in human vascular smooth muscle cells.
- Source :
-
Circulation [Circulation] 2002 Apr 30; Vol. 105 (17), pp. 2030-6. - Publication Year :
- 2002
-
Abstract
- Background: Tissue factor (TF) initiates the extrinsic coagulation cascade leading to thrombin formation. Thrombin induces TF mRNA in vascular smooth muscle cells (VSMCs), thereby contributing to the prolonged procoagulant activity and enhanced thrombogenicity at sites of vascular injury. However, the signaling mechanisms mediating this thrombogenic cycle are unclear. Characteristically, vascular injury promotes the generation of reactive oxygen species (ROS). Because ROS exert signaling functions, we investigated whether the NADPH oxidase, an important source of ROS in VSMCs, contributes to upregulation of TF by thrombin.<br />Methods and Results: Thrombin not only stimulated TF mRNA expression, but also TF-dependent surface procoagulant activity in cultured human VSMCs. This response was attenuated by antioxidants; the flavin inhibitor diphenylene-iodonium, Clostridium difficile toxin B, which inhibits Rho GTPases, p22phox antisense oligonucleotides, or the dominant-negative RacT17N mutant. Inhibitors of p38 MAP kinase and phosphatidylinositol (PI) 3-kinase also prevented thrombin-stimulated TF mRNA expression. Furthermore, thrombin stimulated the phosphorylation of the PI 3-kinase target protein kinase B/Akt in a redox-sensitive and NADPH oxidase-dependent manner.<br />Conclusion: These findings indicate that the NADPH oxidase is essentially involved in the redox-sensitive induction of TF mRNA expression and surface procoagulant activity by thrombin. This response is mediated by NADPH oxidase-dependent activation of p38 MAP kinase and the PI 3-kinase/protein kinase B/Akt pathway. Given that active TF promotes thrombin formation, the NADPH oxidase may play a crucial role in perpetuating the thrombogenic cycle in the injured vessel wall.
- Subjects :
- Bacterial Toxins pharmacology
Cell Membrane metabolism
Cells, Cultured
Enzyme Inhibitors pharmacology
Humans
Kinetics
Mitogen-Activated Protein Kinases antagonists & inhibitors
Mitogen-Activated Protein Kinases metabolism
Muscle, Smooth, Vascular drug effects
Muscle, Smooth, Vascular enzymology
NADPH Dehydrogenase genetics
NADPH Oxidases antagonists & inhibitors
Oligonucleotides, Antisense pharmacology
Phosphoproteins genetics
Protein Kinase Inhibitors
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-akt
RNA, Messenger biosynthesis
Reactive Oxygen Species metabolism
Thromboplastin genetics
Transcriptional Activation drug effects
p38 Mitogen-Activated Protein Kinases
rac GTP-Binding Proteins genetics
rho GTP-Binding Proteins antagonists & inhibitors
Bacterial Proteins
Coagulants pharmacology
Membrane Transport Proteins
Muscle, Smooth, Vascular metabolism
NADPH Oxidases physiology
Protein Serine-Threonine Kinases
Thrombin pharmacology
Thromboplastin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 105
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 11980681
- Full Text :
- https://doi.org/10.1161/01.cir.0000014611.28864.1e