Adenosine Regulates the Proinflammatory Signaling Function of Thrombin in Endothelial Cells

The plasma level of the regulatory metabolite adenosine increases during the activation of coagulation and inflammation. Here we investigated the effect of adenosine on modulation of thrombin‐mediated proinflammatory responses in HUVECs. We found that adenosine inhibits the barrier‐disruptive effect...

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Veröffentlicht in:	Journal of cellular physiology Jg. 229; H. 9; S. 1292 - 1300
Hauptverfasser:	Hassanian, Seyed Mahdi, Dinarvand, Peyman, Rezaie, Alireza R.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Blackwell Publishing Ltd 01.09.2014 Wiley Subscription Services, Inc
Schlagworte:	Adenosine - metabolism Adenosine - pharmacology Adenosine A2 Receptor Agonists - metabolism Adenosine A2 Receptor Agonists - pharmacology Adenosine A2 Receptor Antagonists - pharmacology Adhesion Blood Coagulation - drug effects Capillary Permeability Cell Adhesion Cells, Cultured Coagulation Coculture Techniques Cyclic AMP - metabolism Dose-Response Relationship, Drug E-Selectin - metabolism Enzyme Activation Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - immunology Human Umbilical Vein Endothelial Cells - metabolism Humans Inflammation - blood Inflammation - immunology Inflammation - metabolism Inflammation Mediators - metabolism Intercellular Adhesion Molecule-1 - metabolism Metabolites NF-kappa B - metabolism Protein Transport Receptor, Adenosine A2A - genetics Receptor, Adenosine A2A - metabolism Receptor, Adenosine A2B - metabolism rhoA GTP-Binding Protein - metabolism RNA Interference Signal Transduction - drug effects Thrombin - metabolism Thrombin - pharmacology Transfection Translocation Vascular Cell Adhesion Molecule-1 - metabolism
ISSN:	0021-9541, 1097-4652, 1097-4652
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Zusammenfassung:	The plasma level of the regulatory metabolite adenosine increases during the activation of coagulation and inflammation. Here we investigated the effect of adenosine on modulation of thrombin‐mediated proinflammatory responses in HUVECs. We found that adenosine inhibits the barrier‐disruptive effect of thrombin in HUVECs by a concentration‐dependent manner. Analysis of cell surface expression of adenosine receptors revealed that A2A and A2B are expressed at the highest level among the four receptor subtypes (A2B > A2A > A1 > A3) on HUVECs. The barrier‐protective effect of adenosine in response to thrombin was recapitulated by the A2A specific agonist, CGS 21680, and abrogated both by the siRNA knockdown of the A2A receptor and by the A2A‐specific antagonists, ZM‐241385 and SCH‐58261. The thrombin‐induced RhoA activation and its membrane translocation were both inhibited by adenosine in a cAMP‐dependent manner, providing a molecular mechanism through which adenosine exerts a barrier‐protective function. Adenosine also inhibited thrombin‐mediated activation of NF‐κB and decreased adhesion of monocytic THP‐1 cells to stimulated HUVECs via down‐regulation of expression of cell surface adhesion molecules, VCAM‐1, ICAM‐1, and E‐selectin. Moreover, adenosine inhibited thrombin‐induced elevated expression of proinflammatory cytokines, IL‐6 and HMGB‐1; and chemokines, MCP‐1, CXCL‐1, and CXCL‐3. Taken together, these results suggest that adenosine may inhibit thrombin‐mediated proinflammatory signaling responses, thereby protecting the endothelium from injury during activation of coagulation and inflammation. J. Cell. Physiol. 229: 1292–1300, 2014. © 2014 Wiley Periodicals, Inc.
Bibliographie:	ArticleID:JCP24568 ark:/67375/WNG-ZTN5BX59-L National Institutes of Health - No. HL 101917; No. HL 68571 istex:5A559A70D4F4FFE6B90421C89CE2364380AE4B76 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0021-9541 1097-4652 1097-4652
DOI:	10.1002/jcp.24568