Abstract-There is concern that cyclooxygenase (COX)-2 inhibitors may promote atherothrombosis by inhibiting vascular formation of prostacyclin (PGI 2 ) and an increased thrombotic risk of COX-2 inhibitors has been reported. It is widely accepted that the prothrombotic effects of COX-2 inhibitors can be explained by the removal of platelet-inhibitory PGI 2 .Using microarray chip technology, we have previously demonstrated that thrombomodulin (TM) mRNA is upregulated in cultured human coronary artery smooth muscle cells by the stable prostacyclin mimetic iloprost. This study is the first to demonstrate a stimulation of the expression of functionally active thrombomodulin in human smooth muscle cells by prostaglandins, endogenously formed via the COX-2 pathway. Because TM is an important inhibitor of blood coagulation, these findings provide a novel platelet-independent mechanism to explain the prothrombotic effects of COX-2 inhibitors.
SummaryIt has been proposed that alternatively-spliced human tissue factor (asHTF) is pro-coagulant. We have evaluated the function of asHTF in a mammalian expression system. Full-length human tissue factor (HTF) and asHTF were cloned from smooth muscle cells and over-expressed in HEK293 cells. As expected, a marked pro-coagulant activity (FX activation, thrombin generation) was observed on the surface, in lysates, and on microparticles from HTF transfected cells. In contrast, no pro-coagulant activity of as HTF was observed.
There are two principal cyclooxygenase isoforms referred to as COX-1 and COX-2. Recently, COX-3 has been identified. We have demonstrated the expression of COX-2 in platelets from patients after coronary artery bypass grafting (CABG). Careful biochemical analysis revealed that, when compared to recombinant COX-2, platelet COX-2 had a slightly higher electrophoretic mobility. Two COX-2 sequences (approximately 1.8 kb, approximately 1.7 kb) were cloned from platelet mRNA. The approximately 1.7 kb sequence, designated COX-2a, differed from the human COX-2 sequence only in a deletion from position +458 to +567. Similar to the human COX-3, there is a frame shift in the COX-2a sequence resulting in a TAA stop codon at position +490. Thus, the expression of a COX-2a protein corresponding to the 67 kDa COX-2 protein is not clear. However, the marked shifting from COX-2 to COX-2a in platelets from some patients after CABG is a striking finding.
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