EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: potential impact on atherothrombosis.

Grothusen, C; Umbreen, S; Konrad, I; Stellos, K; Schulz, C; Schmidt, B; Kremmer, E; Teebken, O; Massberg, S; Luchtefeld, M; Schieffer, B; Gawaz, M

doi:10.1161/ATVBAHA.106.138693

journal article

Document type:: Journal Article; Research Support, Non-U.S. Gov't; Article
Author(s):: Grothusen, C; Umbreen, S; Konrad, I; Stellos, K; Schulz, C; Schmidt, B; Kremmer, E; Teebken, O; Massberg, S; Luchtefeld, M; Schieffer, B; Gawaz, M
Title:: EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: potential impact on atherothrombosis.
Abstract:: OBJECTIVE: Thrombus formation after atherosclerotic plaque rupture critically involves the platelet collagen receptor glycoprotein (GP) VI. We investigated the impact of EXP3179, an active metabolite of the angiotensin II type 1 (AT1)-receptor antagonist Losartan (LOS) on GPVI-dependent platelet activation. METHODS AND RESULTS: EXP3179 and LOS but not EXP3174--the major AT1-receptor blocking metabolite of LOS--dose-dependently inhibited collagen-I (P<0.01) and GPVI-dependent platelet aggregation (P<0.01) analyzed by optical aggregometry. Platelet activation was further determined by flow cytometry measuring the expression of platelet PAC-1, an epitope of the activated fibrinogen-receptor complex. EXP3179 and LOS inhibited collagen-I (P<0.01) and GPVI-dependent PAC-1 expression (P<0.01). EXP3179 and LOS but not EXP3174 decreased the adhesion of GPVI-receptor expressing Chinese hamster ovarian cells on collagen-I under arterial shear conditions determined by flow chamber analysis (P<0.01 and P<0.05). EXP3179 also reduced human atherosclerotic plaque material-induced platelet aggregation (P<0.01) in vitro and murine platelet adhesion after acute vessel injury in vivo as determined by intravital microscopy (P<0.01). CONCLUSION: EXP3179 acts as a specific inhibitor of the platelet collagen receptor GPVI independent of AT1-receptor antagonism. Further investigations may clarify its individual potential as a novel pharmacological approach to specifically inhibit atherothrombotic events by GPVI-receptor blockade.
Journal title abbreviation:: Arterioscler Thromb Vasc Biol
Year:: 2007
Journal volume:: 27
Journal issue:: 5
Pages contribution:: 1184-90
Language:: eng
Fulltext / DOI:: doi:10.1161/ATVBAHA.106.138693
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/17347483
Print-ISSN:: 1079-5642
TUM Institution:: I. Medizinische Klinik und Poliklinik (Kardiologie)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Klinik und Poliklinik für Innere Medizin I, Kardiologie (Prof. Laugwitz)2007