on March 8, 2007
Published online before print March 8, 2007, doi: 10.1161/ATVBAHA.106.138693
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Submitted on April 1, 2006
Accepted on February 15, 2007
EXP3179 Inhibits Collagen-Dependent Platelet Activation via Glycoprotein Receptor-VI Independent of AT1-Receptor Antagonism. Potential Impact on Atherothrombosis
Christina Grothusen ;
From Abteilung fuer Kardiologie und Angiologie (C.G., M.L., B.S.), Medizinische Hochschule Hannover; Institut fuer Organische Chemie und Biochemie (S.U., B.S.), Technische Universitaet Darmstadt; Deutsches Herzzentrum und 1. Medizinische Klinik (I.K., C.S., S.M.), Technische Universitaet Muenchen; Medizinische Klinik III (K.S., M.G.), Eberhard-Karls Universitaet Tuebingen; Institut fuer Molekulare Immunologie (E.K.), GSF Forschungszentrum fuer Umwelt und Gesundheit, Muenchen; Abteilung fuer Thorax-, Herz und Gefaesschirurgie (O.T.), Medizinische Hochschule Hannover, Germany.
* To whom correspondence should be addressed. E-mail: Schieffer.Bernhard{at}mh-hannover.de.
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.
Key words: EXP3179 • platelets • collagen • GPVI-receptor • atherothombosis
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