Enhanced release of sphingosine-1-phosphate from hypercholesterolemic platelets: role in development of hypercholesterolemic atherosclerosis.

Although it is well known that sphingosine-1-phosphate (S1P), which induces many biological responses, is present in plasma and is mainly released from activated platelets, little is known whether the release of S1P is increased when platelets are activated in the hypercholesterolemic condition, and what are the roles of increased S1P generation in the development or progression of the atherosclerosis. Results show that 0.5% cholesterol diet for 16 weeks induces platelet hyperaggregability to low doses of agonists as well as development of hypercholesterolemic atherosclerosis in the rabbits. The generation and released level of S1P were significantly increased in the hypersensitized platelets and blood plasma in hypercholesterolemic rabbits. We also demonstrated that S1P increased VSMC proliferation via endothelial differentiation gene (EDG)-1 receptor dependent pathway. Our results indicate that release of S1P from activated platelets was increased by enhanced platelet sensitivity in hypercholesterolemia, which potentiated the ox-LDL-induced VSMC proliferation via EDG-1 receptor pathway.