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)G2 and
PGH2 from arachidonic acid (AA) by the COX and peroxidase activities of the enzymes,
respectively. PGH2 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)A2, 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 TXA2 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 PGE2 and PGI2 (prostacyclin), in inflammatory cells. However, PGI2 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 TXA2 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 PGD2, 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.