The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice - Evidence that eicosanoids other than thromboxane contribute to atherosclerosis

Atherosclerosis involves a complex array of factors, including leukocyte ad hesion and platelet vasoactive factors. Aspirin, which is used to prevent s econdary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidoni c acid products, such as prostaglandin (PG) H-2, PGF(2 alpha), hydroxyeicos atetraenoic acids, and isoprostanes, can be effectively antagonized by bloc king thromboxane (TP) receptors. The purpose of this study 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 ST8886. The effect of 11 weeks of treatment with aspirin (30 mg(.)kg(-1.)d(-1)) or S18886 (5 mg(.)kg(-1.)d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabo lite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks o f age. Both treatments did not affect body or heart weight or serum cholest erol levels. Aspirin, to a greater extent than S18886, significantly decrea sed serum TxB(2) levels, indicating the greater efficacy of aspirin in prev enting 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 significan t effect on atherogenesis or adhesion molecule levels, The effects of S1888 6 suggest that blockade of TP receptors inhibits atherosclerosis by a mecha nism independent of platelet-derived TxA(2), perhaps by preventing the expr ession of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).