Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo
| Autor: | Jean-Marc Herbert, F. Dol, C. Avril, Françoise Bono, J.-P. Herault, Paul Schaeffer, A.M. Mares |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Serine Proteinase Inhibitors
Platelet-derived growth factor Vascular smooth muscle Survivin Blotting Western Receptors Cell Surface Naphthalenes Biology Phosphatidylinositols Hemostatics Inhibitor of Apoptosis Proteins chemistry.chemical_compound Thrombin Epidermal growth factor medicine Animals Homeostasis Humans Binding site Antibodies Blocking Receptor Cells Cultured Platelet-Derived Growth Factor Epidermal Growth Factor Factor X Muscle Smooth General Medicine Immunohistochemistry Molecular biology Carotid Arteries chemistry Biochemistry Factor Xa biology.protein Endothelium Vascular Rabbits Propionates Carotid Artery Injuries Peptides Platelet-derived growth factor receptor Factor Xa Inhibitors Protein Binding Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 101:993-1000 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci1833 |
| Popis: | The binding of 125I-factor Xa to human aortic smooth muscle cell (SMC) monolayers was studied. At 4 degreesC, 125I-factor Xa bound to a single class of binding sites with a dissociation constant value of 3.6+/-0.7 nM and a binding site density of 11,720+/-1,240 sites/cell (n = 9). 125I-factor Xa binding was not affected by factor X, thrombin, or by DX9065, a direct inhibitor of factor Xa, but was inhibited by factor Xa (IC50 = 5.4+/-0.2 nM; n = 9) and by antibodies specific for the effector cell protease receptor 1 (EPR-1), a well-known receptor of factor Xa on various cell types. A factor X peptide duplicating the inter-EGF sequence Leu83-Leu88-(Gly) blocked the binding of 125I-factor Xa to these cells in a dose-dependent manner (IC50 = 110+/-21 nM). Factor Xa increased phosphoinositide turnover in SMCs and when added to SMCs in culture was a potent mitogen. These effects were inhibited by DX9065 and by antibodies directed against EPR-1 and PDGF. Increased expression of EPR-1 was identified immunohistochemically on SMCs growing in culture and in SMCs from the rabbit carotid artery after vascular injury. When applied locally to air-injured rabbit carotid arteries, antibodies directed against EPR-1 (100 mug/ artery) strongly reduced myointimal proliferation 14 d after vascular injury (65-71% inhibition, P < 0.01). DX9065 (10 mg/kg, subcutaneous) inhibited myointimal proliferation significantly (43% inhibition, P < 0.05). These findings indicate that SMCs express functional high affinity receptors for factor Xa related to EPR-1, which may be of importance in the regulation of homeostasis of the vascular wall and after vascular injury. |
| Databáze: | OpenAIRE |
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