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  • Title: Transcellular formation of thromboxane A(2) in mixed incubations of endothelial cells and aspirin-treated platelets strongly depends on the prostaglandin I-synthase activity.
    Author: Camacho M, Vila L.
    Journal: Thromb Res; 2000 Jul 15; 99(2):155-64. PubMed ID: 10946089.
    Abstract:
    Despite an almost total suppression of platelet cyclooxygenase (COX) by aspirin, as monitored ex vivo, incomplete suppression of thromboxane (Tx)A(2) metabolite excretion has been detected in some patients with unstable angina treated with low doses of aspirin. A plausible explanation for this finding is the transcellular formation of TxA(2) by platelets from prostaglandin H(2) released by endothelial cells. We recently reported that probably only COX and PGI-synthase (PGIS) are involved in the biosynthesis of prostanoids in endothelial cells. The present work was thus focused to ascertain the dependence of the transcellular biosynthesis of TxA(2), by endothelial cells and aspirin-treated platelets, on the relative activity of these enzymes. Synthesis of eicosanoids from exogenous and endogenous arachidonic acid (AA) by mixed incubations of human umbilical vein endothelial cells (HUVEC) in culture and aspirin-treated platelets were determined by HPLC and enzyme immune assay. The ratio of COX to PGIS activities was modified in HUVEC by treatment with interleukin-1beta (IL-1beta). Transcellular formation of TxA(2) was only relevant when HUVEC overexpressed COX-2 (monitored by RT-PCR and Western blotting), and in these conditions TxA(2) formation started 2 minutes after substrate addition. Progression curves showed that half-times (t(1/2)) of the COX and PGIS activity were 2.73 and 0.47 minutes, respectively, in resting HUVEC, whereas these values for IL-1beta-treated cells were 1.33 and 0.07 minutes, respectively, indicating that expression of COX-2 increased the rate of PGIS "suicide" inactivation. Collectively, these results indicated that not only enhanced COX activity but also substantial PGIS inactivation was required for significant transcellular biosynthesis of TxA(2).
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