Aspirin insensitive eicosanoid biosynthesis in cardiovascular disease.

Inhibition of platelet cyclooxygenase (COX)-1 is involved in aspirin cardioprotection observed in clinical trials, but, in some patients, aspirin is unable to protect from thrombotic complications. An incomplete suppression of platelet thromboxane (TX) A2 biosynthesis has been assumed to participate in the phenomenon of aspirin resistance, as a consequence of the following possible mechanisms: (i) COX-2 expression in newly formed platelets; (ii) pharmacodynamic interactions between aspirin and coadministered nonsteroidal antiinflammatory drugs (e.g. ibuprofen); (iii) expression of variant isoforms of COX-1 with reduced sensitivity to irreversible inactivation at Ser529. Furthermore, aspirin failure may be due to enhanced formation of vasoactive and/or proaggregatory eicosanoids despite an almost complete suppression of platelet TXA2 biosynthesis by aspirin. Thus, in a subset of patients with unstable angina treated with low-dose aspirin, to almost completely block platelet COX-1 activity, enhanced TXA2 biosynthesis in vivo has been demonstrated, presumably through an increased generation of COX-2-dependent PGH2 in plaque monocytes/macrophages or activated vascular cells. The concomitant increased formation of 8-iso-PGF2alpha, one of the most abundant F2-isoprostanes in humans, generated by free-radical catalyzed arachidonate peroxidation, may be involved in aspirin resistance because of its capacity to induce platelet and vascular smooth muscle cell activation through the interaction with thromboxane receptors (TPs). Finally, enhanced production of vasoactive cysteinyl leukotrienes (cys-LTs) occurs in unstable angina despite conventional antithrombotic and antianginal treatment. The use of selective pharmacological tools (i.e. highly selective COX-2 inhibitors, TP antagonists, cys-LT inhibitors and antagonists) will allow to ascertain the contribution of aspirin insensitive eicosanoid biosynthesis in aspirin cardioprotective failure.