Production of prostaglandin E2 induced by cigarette smoke modulates tissue factor expression and activity in endothelial cells

Cigarette smoke (CS) increases the incidence of atherothrombosis, the release of prostaglandin (PG) E-2, and the amount of tissue factor (TF). The link between PGE(2) and TF, and the impact of this interaction on CS-induced thrombosis, is unknown. Plasma from active smokers showed higher concentration of PGE(2), TF total antigen, and microparticle-associated TF (MP-TF) activity compared with never smokers. Similar results were obtained in mice and in mouse cardiac endothelial cells (MCECs) after treatment with aqueous CS extracts (CSEs) plus IL-1 beta [CSE (6.4 puffs/L)/IL-1 beta (2 mu g/L)]. A significant correlation between PGE(2) and TF total antigen or MP-TF activity were observed in both human and mouse plasma or tissue. Inhibition of PGE synthase reduced TF in vivo and in vitro and prevented the arterial thrombosis induced by CSE/IL-1 beta. Only PG E receptor 1 (EP1) receptor antagonists (SC51089:IC50 similar to 1 mu M, AH6809:IC50 similar to 7.5 mu M) restored the normal TF and sirtuin 1 (SIRT1) levels in MCECs before PGE(2) (EC50 similar to 2.5 mM) or CSE/IL-1 beta exposure. Similarly, SIRT1 activators (CAY10591:IC50 similar to 10 mu M, resveratrol: IC50 similar to 5 mu M) or prostacyclin analogs (IC50 similar to 5 mM) prevented SIRT1 inhibition and reduced TF induced by CSE/IL-1 beta or by PGE2. In conclusion, PGE2 increases both TF expression and activity through the regulation of the EP1/SIRT1 pathway. These findings suggest that EP1 may represent a possible target to prevent prothrombotic states.