Abstract
BACKGROUND: Proinflammatory cytokines are associated with cardiovascular diseases, including acute and recurrent myocardial infarction. However, the causal role of cytokines in thrombotic complications of atherosclerosis remains unclear. Interleukin-1β (IL-1β) is currently being targeted in a human clinical trial for the prevention of ischemic events. OBJECTIVES: The purpose of the present study was to test the role of IL-1β in arterial thrombosis and a potential protective effect of P-selectin glycoprotein ligand-1 (Psgl-1) deficiency. METHODS AND RESULTS: Wild-type and Psgl-1-deficient mice were treated with IL-1β and then subjected to carotid photochemical injury to induce thrombosis. IL-1β shortened the time to thrombosis in wild-type mice, while Psgl-1(-/-) mice were protected from the prothrombotic effects of IL-1β. A neutralizing antibody to Psgl-1 was also effective in protecting against the prothrombotic effects of IL-1β. The protective effect of Psgl-1 deficiency was associated with reduced plasma levels of soluble P-selectin and collagen-stimulated whole blood aggregation. CONCLUSIONS: Our data demonstrate that Psgl-1 deficiency is protective against the prothrombotic effects of IL-1β and suggest that Psgl-1 inhibition may be a useful treatment strategy for targeting vascular thrombosis associated with enhanced inflammatory states.