Cyclooxygenases and platelet functions.

Cyclooxygenase (COX) isozymes, i.e., COX-1 and COX-2, are encoded by separate genes and are involved in the generation of the same products, prostaglandin (PG)G and PGH from arachidonic acid (AA) by the COX and peroxidase activities of the enzymes, respectively. PGH is then transformed into prostanoids in a tissue-dependent fashion due to the different expression of downstream synthases. Platelets present almost exclusively COX-1, which generates large amounts of thromboxane (TX)A, a proaggregatory and vasoconstrictor mediator. This prostanoid plays a central role in atherothrombosis, as shown by the benefit of the antiplatelet agent low-dose aspirin, a preferential inhibitor of platelet COX-1. Recent findings have shown the relevant role played by platelets and TXA in developing chronic inflammation associated with several diseases, including tissue fibrosis and cancer. COX-2 is induced in response to inflammatory and mitogenic stimuli to generate PGE and PGI (prostacyclin), in inflammatory cells. However, PGI is constitutively expressed in vascular cells in vivo and plays a crucial role in protecting the cardiovascular systems due to its antiplatelet and vasodilator effects. Here, platelets' role in regulating COX-2 expression in cells of the inflammatory microenvironment is described. Thus, the selective inhibition of platelet COX-1-dependent TXA by low-dose aspirin prevents COX-2 induction in stromal cells leading to antifibrotic and antitumor effects. The biosynthesis and functions of other prostanoids, such as PGD, and isoprostanes, are reported. In addition to aspirin, which inhibits platelet COX-1 activity, possible strategies to affect platelet functions by influencing platelet prostanoid receptors or synthases are discussed.