Elsevier

Thrombosis Research

Volume 91, Issue 2, 15 July 1998, Pages 57-64
Thrombosis Research

REGULAR ARTICLE
Adenosine Regulates Tissue Factor Expression on Endothelial Cells

https://doi.org/10.1016/S0049-3848(98)00045-0Get rights and content

Abstract

The aim of this study was to evaluate the inhibitory activity of adenosine on tumor necrosis factor-α (TNF), thrombin-, or phorbol 12-myristate 13-acetate (PMA)-induced tissue factor (TF) expression on human 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 (A1, A2a, A2b, and A3) in this regulation, we evaluated the effect of several agonists and antagonists specific for AR-subclass on TF expression. The selective A2aAR agonist, 2-p-(2-carboxyethyl) phenethylamino-5′-N-ethylcarboxamido adenosine hydrochloride (CGS 21680), the A3AR agonist, N6-2-(4-aminophenyl) ethyladenosine (APNEA), and the A1AR antagonist, 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine (PACPX) each inhibited TF activity expression induced by TNF, thrombin, or PMA on HUVECs. In contrast, the selective A1AR agonist, chloro-N6-cyclopentyladenosine (CCPA) and the A2AR antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX) enhanced each stimulant-induced TF activity expression. All agonist or antagonist alone did not alter the basal TF 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 endothelial cells via its A2a and A3 receptors, particularly during ischemic or atherosclerotic processes which are known to be associated with local increased levels of adenosine.

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Materials

Blood coagulation factor VIIa and factor X were kindly provided by Dr. Tomohiro Nakagaki of the Chemo-Sero-Theraputic Reserch Institute (Kumamoto, Japan). Thrombin was purchased from the Green Cross Corporation (Osaka, Japan). Recombinant human TNF was donated by the Asahi Chemical Industry (Shizuoka, Japan). The synthetic peptide substrate of factor Xa, N-benzoyl-L - isoleucyl - L - glutamyl - glycyl - L - arginine - p - nitro -anilide hydrochloride (S2222) was purchased from Chromogenix

Effect of Adenosine on the TF Activity on HUVECs Induced by TNF, Thrombin, or PMA

We previously reported that TNF, thrombin, and PMA induced TF expression on HUVECs in a dose- and time-dependent fashion [20]. In agreement with this, in the current study, TNF (1000 U/mL), thrombin (12.5 nM), or PMA (2.5 nM) induced TF expression on HUVEC surface, respectively (Figure 1A). Increasing concentrations of adenosine (0 to 10 μM) decreased TF activity in a dose-dependent fashion (Figure 1B). Incubation with 10 μM adenosine decreased the TF activity induced by TNF, thrombin, or PMA

Discussion

Adenosine is an active biological compound that modulates various physiological mechanisms such as cardiovascular tone and immune responses 1, 2, 3. During ischemic or chronic atherosclerotic processes, adenosine increases locally up to micromolar levels. It exerts anti-inflammatory and cytoprotective effects 1, 2, 3. In the current study, physiological concentrations of adenosine down-regulated the endothelial TF expression induced by TNF, thrombin, or PMA. This adenosine effect was

Acknowledgements

This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Culture and Sports of Japan (No. 09281215, 09480149, 09877206).

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