Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells
| Autor: | Gen Tohda, Shotaro Kosaka, Sadao Takahashi, Hidemi Ishii, Eiko Okada, Yoshikatsu Okada, Isamu Miyamori, Koji Oida |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Male
Pathology medicine.medical_specialty Vascular smooth muscle Arteriosclerosis Thrombomodulin Biology Naphthalenes Muscle Smooth Vascular law.invention law Epidermal growth factor Thrombin receptor medicine Animals Humans Rats Wistar Aged DNA Middle Aged Molecular biology Recombinant Proteins Rats Endothelial stem cell ErbB Receptors Cell culture Calcium-Calmodulin-Dependent Protein Kinases Recombinant DNA Immunohistochemistry Female Mitogens Cardiology and Cardiovascular Medicine Cell Division Thymidine |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 18(12) |
| ISSN: | 1079-5642 |
| Popis: | Abstract —Thrombomodulin (TM), a thrombin receptor protein found on the endothelial cell surface, contains 6 tandem epidermal growth factor (EGF)–like structures. Recombinant human TM peptide containing these 6 EGF-like domains (rTM e 1–6) exhibits mitogenic activity in Swiss 3T3 cells. We examined the localization of TM in atherosclerotic lesions and the effects of rTM e 1–6 on the growth of cultured rat vascular smooth muscle cells (SMCs). Immunohistochemical analysis demonstrated that TM antigen was localized on monocytes, macrophages, and vascular SMCs. In cultured vascular SMCs, rTM e 1–6 accelerated [ 3 H]thymidine uptake into DNA in a dose-dependent manner up to 3.4 times the control level. This mitogenic activity was abolished by addition of polyclonal anti-human TM antibody. The rTM e 1–6–induced mitogenesis was enhanced by EGF. However, a neutralizing monoclonal antibody against the EGF receptor (monoclonal antibody 225) did not inhibit the mitogenic activity of rTM e 1–6. Calphostin C, a specific protein kinase C inhibitor, and lavendustin-A, an inhibitor of EGF receptor–specific protein tyrosine kinase, inhibited the mitogenic activities of both rTM e 1–6 and EGF. Finally, rTM e 1–6 treatment increased the level of phosphorylated mitogen-activated protein kinase in SMCs. Together, these results suggest that TM expression in atherosclerotic lesions may be associated with promotion of atherosclerosis through its mitogenic activity in vascular SMCs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|