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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1083-1090.)
© 1999 American Heart Association, Inc.

Original Contributions

Adhesive Interaction Between P-Selectin and Sialyl Lewis^x Plays an Important Role in Recurrent Coronary Arterial Thrombosis in Dogs

Hisao Ikeda; Takahisa Ueyama; Toyoaki Murohara; Hideo Yasukawa; Nobuya Haramaki; Hiroyuki Eguchi; Atsushi Katoh; Yoshinori Takajo; Ichiro Onitsuka; Takafumi Ueno; Shinichiro J. Tojo; Tsutomu Imaizumi

From the Department of Internal Medicine III (H.I., T.U., T.M., H.Y., N.H., H.E., A.K., Y.T., I.O., T.U., T.I.) Kurume University School of Medicine, Kurume, Japan; and Sumitomo Pharmaceuticals Research Center (S.J.T.), Osaka, Japan.

Correspondence to Hisao Ikeda, MD, PhD, Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830, Japan. E-mail ikeikeda{at}med.kurume-u.ac.jp

Abstract—Cell adhesion molecules may play an important role in the disease process of acute coronary syndromes. We have shown a neutralizing anti-P-selectin monoclonal antibody and a sialyl Lewis^x-containing oligosaccharide (SLe^x-OS), an analogue of selectin ligand on leukocytes, reduce cyclic flow variations (CFVs) in a canine model of recurrent coronary arterial thrombosis, suggesting the important interaction between P-selectin and SLe^x for the pathophysiology of these syndromes. However, the functional role of these adhesion molecules in the thrombotic process remains unclear. Therefore, we investigated effects of SLe^x-OS on CFVs, platelet P-selectin expression, and morphology of the stenotic site in the same model. Anesthetized open-chest dogs (n=34) were randomly divided into 4 groups after developing CFVs. Dogs intravenously received saline or graded doses of SLe^x-OS (5, 20, or 40 mg/kg bolus) infusion followed by a continuous infusion (5 mg · kg^-1 · h^-1) for 60 minutes. By flow cytometric analysis, P-selectin expression on platelets after CFVs was significantly upregulated during CFVs. Immunohistochemical analysis revealed the incorporation of platelets with upregulated P-selectin within thrombi at the stenotic site. Microscopic observations revealed the presence of numerous platelets adhered to leukocytes at the stenotic site on the damaged endothelium. SLe^x-OS significantly reduced CFVs, inhibited the P-selectin expression on platelets, and prevented the adherence of platelets and leukocytes. These findings further support the notion that the adhesive interaction between P-selectin on platelets and SLe^x on leukocytes plays an important role in platelet-mediated thrombus formation in this model.

Key Words: thrombosis • platelets • leukocytes • P-selectin • sialyl Lewis^x

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