TP Receptors and Oxidative Stress Hand in Hand from Endothelial Dysfunction to Atherosclerosis

Thromboxane A(2) and the activation of TP receptors that it causes play an important role in platelet aggregation and therefore in thrombosis. However, TP receptors are also involved in the pathologies of the vascular wall including impaired endothelium-dependent vasodilation, increased oxidant generation, and increased expression of adhesion molecules. The beneficial effects of TP antagonists on the vascular wall attenuate these features of vascular disease. They are not shared by aspirin. In fact, TP antagonists are active in patients treated with aspirin, indicating that their potential beneficial effects are mediated by mechanisms different from the antithrombotic actions of aspirin. Our studies have demonstrated the vascular benefits of TP antagonists in experimental animals, particularly in models of diabetes mellitus, in which elevated levels of eicosanoids play a role not only in vascular pathologies but also in those of the kidney and other tissues. They suggest that TP blockade protects against fundamental and widespread tissular dysfunction associated with metabolic disease including hyperlipidemia and hyperglycemia. TP receptor antagonists represent a promising avenue for the prevention of vascular disease in part because of these pleiotropic actions that extend beyond their antithrombotic properties.