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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1184.)
© 2007 American Heart Association, Inc.

Thrombosis

EXP3179 Inhibits Collagen-Dependent Platelet Activation via Glycoprotein Receptor-VI Independent of AT₁-Receptor Antagonism

Potential Impact on Atherothrombosis

Christina Grothusen; Sumaira Umbreen; Ildiko Konrad; Konstantinos Stellos; Christian Schulz; Boris Schmidt; Elisabeth Kremmer; Omke Teebken; Steffen Massberg; Maren Luchtefeld; Bernhard Schieffer; Meinrad Gawaz

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.

Correspondence to Bernhard Schieffer, MD, Abt. fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. E-mail Schieffer.Bernhard{at}mh-hannover.de; or Meinrad Gawaz, MD, Medizinische Klinik III, Eberhard-Karls Universitaet Tuebingen, Otfried-Müller-Str. 10, 72076 Tuebingen, Germany. E-mail meinrad.gawaz@med.uni-tuebingen.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.

This study investigated the impact of EXP3179, an active metabolite of Losartan on collagen-induced platelet activation via the GPVI-receptor. EXP3179 inhibits collagen-dependent platelet activation by GPVI-receptor blockade independent of AT₁-receptor antagonism, suggesting a novel role for EXP3179 as a platelet-inhibitory agent.

Key Words: EXP3179 • platelets • collagen • GPVI-receptor • atherothombosis

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