EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: potential impact on atherothrombosis.
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.
Grothusen
Christina
C
Abt. fuer Kardiologie und Angiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Umbreen
Sumaira
S
Konrad
Ildiko
I
Stellos
Konstantinos
K
Schulz
Christian
C
Schmidt
Boris
B
Kremmer
Elisabeth
E
Teebken
Omke
O
Massberg
Steffen
S
Luchtefeld
Maren
M
Schieffer
Bernhard
B
Gawaz
Meinrad
M
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
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