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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1998;18:1861-1869.)
© 1998 American Heart Association, Inc.

Original Contributions

Expression of Thrombomodulin in Atherosclerotic Lesions and Mitogenic Activity of Recombinant Thrombomodulin in Vascular Smooth Muscle Cells

Gen Tohda; Koji Oida; Yoshikatsu Okada; Shotaro Kosaka; Eiko Okada; Sadao Takahashi; Hidemi Ishii; Isamu Miyamori

From the Third Department of Internal Medicine, Faculty of Medicine, Fukui Medical University, Fukui, Japan (G.T., K.O., S.K., E.O., S.T., I.M.); the Department of Pathology, Osaka Medical College, Osaka, Japan (Y.O.); and the Department of Public Health, Showa College of Pharmaceutical Sciences, Tokyo, Japan (H.I.).

Correspondence to Koji Oida, MD, Third Department of Internal Medicine, Fukui Medical University, Matsuoka-cho, Fukui 910-11, Japan. E-mail kojio{at}fmsrsa.fukui-med.ac.jp

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 (rTME1–6) exhibits mitogenic activity in Swiss 3T3 cells. We examined the localization of TM in atherosclerotic lesions and the effects of rTME1–6 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, rTME1–6 accelerated [³H]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 rTME1–6–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 rTME1–6. 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 rTME1–6 and EGF. Finally, rTME1–6 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.

Key Words: atherosclerosis • thrombomodulin • smooth muscle cells

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