ADENOSINE REGULATES TISSUE FACTOR EXPRESSION ON ENDOTHELIAL-CELLS

The aim of this study was to evaluate the inhibitory activity of adeno sine on tumor necrosis factor-alpha (TNF), thrombin-, or phorbol 12-my ristate 13-acetate (PMA)-induced tissue factor (TF) expression on huma n umbilical vein endothelial cells (HUVECs). This inhibitory effect of adenosine was found to be counteracted by the non-selective adenosine receptor (AR) antagonist, 8-(p-sulfophenyl) theophylline. To clarify the role of ARs (Al, A2a, A2b, and A3) in this regulation, we evaluate d the effect of several agonists and antagonists specific for AR-subcl ass on TF expression. The selective A2aAR agonist, 2-p-(2-carboxyethyl ) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21 680), the A3AR agonist, N6-2-(4-aminophenyl) ethyladenosine (APNEA), a nd the A1AR antagonist, 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthi ne (PACPX) each inhibited TF activity expression induced by TNF, throm bin, or PMA on HUVECs. In contrast, the selective A1AR agonist, chloro -N6-cyclopentyladenosine (CCPA) and the A2AR antagonist, 3,7-dimethyl- l-propargylxanthine (DMPX) enhanced each stimulant-induced TF activity expression. All agonist or antagonist alone did not alter the basal T F expression on HUVECs. Our results suggest that stimulation of A2aAR and A3AR down-regulates and that of A1AR up-regulates the endothelial cell TF expression induced by TNF, PMA, or thrombin. Thus, it appears that adenosine itself may exert anticoagulant activity on vascular end othelial cells via its A2a and A3 receptors, particularly during ische mic or atherosclerotic processes which are known to be associated with local increased levels of adenosine. (C) 1998 Elsevier Science Ltd.