Thromboxane and the thromboxane receptor in cardiovascular disease

Abstract

Thromboxane A(2) (TXA(2)), the primary product of COX-1-dependent metabolism of arachidonic acid, mediates its biological actions through the TXA(2) receptor, termed the TP. Irreversible inhibition of platelet COX-1-derived TXA(2) with low-dose aspirin affords protection against primary and secondary vascular thrombotic events, underscoring the central role of TXA(2) as a platelet agonist in cardiovascular disease. The limitations associated with aspirin use include significant gastrointestinal toxicity, bleeding complications, potential interindividual response variability and poor efficacy in some disease states. This, together with the broad role of TXA(2) in cardiovascular disease beyond the platelet, has refocused interest towards additional TXA(2)-associated drug targets, in particular TXA(2) synthase and the TP. The superiority of these agents over low-dose aspirin, in terms of clinical efficacy, tolerability and commercial viability, remain open questions that are the focus of ongoing research.

Figure 1. Simplified scheme of TXA₂ generation and TP signaling

Platelet COX-1-dependent metabolism of AA is the dominant source of TXA₂. Activation of the TP (agonists shown in pale blue boxes) induces biological effects that drive CVD. Multiple signaling pathways have been described for TP but the primary ones associated with TXA₂ biological function are activation of RhoA or PLCβ. ROS-dependent upregulation of TP expression may increase TXA₂/isoprostane responses during CVD/oxidant stress. TP signaling is limited by its desensitization and downregulation. AA: Arachidonic acid; EC: Endothelial cell; PGH₂: Prostaglandin H₂; ROS: Reactive oxygen species; TP: TXA₂ receptor; TXA₂: Thromboxane A₂; TXAS: TCA₂ synthase.