This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/5/1184    most recent ATVBAHA.106.138693v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Grothusen, C. Articles by Gawaz, M. Search for Related Content PubMed PubMed Citation Articles by Grothusen, C. Articles by Gawaz, M.

(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