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

被引:40
作者
Grothusen, Christina
Umbreen, Sumaira
Konrad, Ildiko
Stellos, Konstantinos
Schulz, Christian
Schmidt, Boris
Kremmer, Elisabeth
Teebken, Omke
Massberg, Steffen
Luchtefeld, Maren
Schieffer, Bernhard
Gawaz, Meinrad
机构
[1] Hannover Med Sch, Abt Kardiol & Angiol, D-30625 Hannover, Germany
[2] Tech Univ Darmstadt, Inst Organ Chem & Biochem, D-64287 Darmstadt, Germany
[3] Tech Univ Munich, Med Klin 1, D-8000 Munich, Germany
[4] Tech Univ Munich, Deutsch Herzzentrum, D-8000 Munich, Germany
[5] Univ Tubingen, Med Klin 3, Tubingen, Germany
[6] GSF Forschungszentrum Umwelt & Gesundheit, Inst Mol Immunol, Munich, Germany
[7] Hannover Med Sch, Abt Thorax Herz & Gefaesschirurg, D-30625 Hannover, Germany
关键词
EXP3179; platelets; collagen; GPVI-receptor; atherothombosis;
D O I
10.1161/ATVBAHA.106.138693
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (AT(1))-receptor antagonist Losartan (LOS) on GPVI-dependent platelet activation. Methods and Results - EXP3179 and LOS but not EXP3174 - the major AT(1)-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 AT(1)-receptor antagonism. Further investigations may clarify its individual potential as a novel pharmacological approach to specifically inhibit atherothrombotic events by GPVI-receptor blockade.
引用
收藏
页码:1184 / 1190
页数:7
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