The Thromboxane Receptor Antagonist S18886 but Not Aspirin Inhibits Atherogenesis in Apo E-Deficient Mice : Evidence That Eicosanoids Other Than Thromboxane Contribute to Atherosclerosis
Arteriosclerosis, Thrombosis and Vascular Biology
Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A 2 . The actions of TxA 2 as well as of other arachidonic acid products, such as prostaglandin (PG) H 2 , PGF 2␣ , hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this
... udy was to determine the role of platelet-derived TxA 2 in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) or S18886 (5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA 2 metabolite TxB 2 was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB 2 levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA 2 . S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA 2 synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA 2 , perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA 2 .