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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Abt. fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Grothusen
authors.forename: Sumaira
authors.initials: S
authors.lastname: Umbreen
authors.forename: Ildiko
authors.initials: I
authors.lastname: Konrad
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stellos
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Omke
authors.initials: O
authors.lastname: Teebken
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Maren
authors.initials: M
authors.lastname: Luchtefeld
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D050197:Atherosclerosis / Q000097:blood / Q000150:complications*; D005434:Flow Cytometry; D006801:Humans; D019808:Losartan / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008856:Microscopy, Fluorescence; D010974:Platelet Aggregation / Q000187:drug effects*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D010980:Platelet Membrane Glycoproteins; D044140:Receptor, Angiotensin, Type 1; C098341:platelet membrane glycoprotein VI; C073600:2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxaldehyde; D019808:Losartan