Adhesive interaction between P-selectin and sialyl Lewis(x) plays an important role in recurrent coronary arterial thrombosis in dogs

Cell adhesion molecules may play an important role in the disease process o f acute coronary syndromes. We have shown a neutralizing anti-P-selectin mo noclonal antibody and a sialyl Lewis(x)-containing oligosaccharide (SLe(x)- OS), an analogue of selectin ligand on leukocytes, reduce cyclic flow varia tions (CFVs) in a canine model of recurrent coronary arterial thrombosis, s uggesting the important interaction between P-selectin and SLe(x) for the p athophysiology of these syndromes. However, the functional role of these ad hesion molecules in the thrombotic process remains unclear. Therefore, we i nvestigated effects of SLe(x)-OS on CFVs, platelet P-selectin expression, a nd morphology of the stenotic site in the same model. Anesthetized open-che st dogs (n=34) were randomly divided into 4 groups after developing CFVs. D ogs intravenously received saline or graded doses of SLe(x)-OS (5, 20, or 4 0 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 o n platelets after CFVs was significantly upregulated during CFVs. Immunohis tochemical analysis revealed the incorporation of platelets with upregulate d P-selectin within thrombi at the stenotic site. Microscopic observations revealed the presence of numerous platelets adhered to leukocytes at the st enotic site on the damaged endothelium. SLe(x)-OS significantly reduced CFV s, inhibited the P-selectin expression on platelets, and prevented the adhe rence of platelets and leukocytes. These findings further support the notio n that the adhesive interaction between P-selectin on platelets and SLe(x) on leukocytes plays an important role in platelet-mediated thrombus formati on in this model.