EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism: potential impact on atherothrombosis

Arterioscler Thromb Vasc Biol. 2007 May;27(5):1184-90. doi: 10.1161/ATVBAHA.106.138693. Epub 2007 Mar 8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Atherosclerosis / blood
  • Atherosclerosis / complications*
  • Flow Cytometry
  • Humans
  • Losartan / analogs & derivatives*
  • Losartan / therapeutic use
  • Microscopy, Fluorescence
  • Platelet Aggregation / drug effects*
  • Platelet Membrane Glycoproteins / antagonists & inhibitors
  • Platelet Membrane Glycoproteins / metabolism*
  • Receptor, Angiotensin, Type 1 / drug effects
  • Thrombosis* / blood
  • Thrombosis* / etiology
  • Thrombosis* / prevention & control
  • Treatment Outcome


  • Angiotensin II Type 1 Receptor Blockers
  • Platelet Membrane Glycoproteins
  • Receptor, Angiotensin, Type 1
  • platelet membrane glycoprotein VI
  • 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxaldehyde
  • Losartan