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
相关论文
共 30 条
  • [1] BAUMGARTNER HR, 1977, THROMB HAEMOSTASIS, V37, P1
  • [2] Expression of platelet collagen receptor glycoprotein VI is associated with acute coronary syndrome
    Bigalke, Boris
    Lindemann, Stephan
    Ehlers, Raila
    Seizer, Peter
    Daub, Karin
    Langer, Harald
    Schonberger, Tanja
    Kremmer, Elisabeth
    Siegel-Axel, Dorothea
    May, Andreas E.
    Gawaz, Meinrad
    [J]. EUROPEAN HEART JOURNAL, 2006, 27 (18) : 2165 - 2169
  • [3] Surface expression of collagen receptor Fc receptor-γ/glycoprotein VI is enhanced on platelets in type 2 diabetes and mediates release of CD40 ligand and activation of endothelial cells
    Cabeza, N
    Li, ZY
    Schulz, C
    Kremmer, E
    Massberg, S
    Bültmann, A
    Gawaz, M
    [J]. DIABETES, 2004, 53 (08) : 2117 - 2121
  • [4] 4,9,16,21-TETRAMETHYL-5,7,17,19-TETRAKISDEHYDRO[14]-ANNULENO[14]ANNULENE, A MACROCYCLIC ANALOG OF NAPHTHALENE
    CRESP, TM
    SONDHEIMER, F
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1975, 97 (15) : 4412 - 4413
  • [5] Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE):: a randomised trial against atenolol
    Dahlöf, B
    Devereux, RB
    Kjeldsen, SE
    Julius, S
    Beevers, G
    de Faire, U
    Fyhrquist, F
    Ibsen, H
    Kristiansson, K
    Lederballe-Pedersen, O
    Lindholm, LH
    Nieminen, MS
    Omvik, P
    Oparil, S
    Wedel, H
    [J]. LANCET, 2002, 359 (9311) : 995 - 1003
  • [6] Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAL randomised trial
    Dickstein, K
    Kjekshus, J
    [J]. LANCET, 2002, 360 (9335) : 752 - 760
  • [7] Fateh-Moghadam S, 2000, CIRCULATION, V102, P890
  • [8] The role of the platelet glycoprotein IIb/IIIa in thrombosis and haemostasis
    Fullard, JF
    [J]. CURRENT PHARMACEUTICAL DESIGN, 2004, 10 (14) : 1567 - 1576
  • [9] Comparison of effects of Clopidogrel versus ticlopidine on platelet function in patients undergoing coronary stent placement
    Gawaz, M
    Seyfarth, M
    Müller, I
    Rüdiger, S
    Pogatsa-Murray, G
    Wolf, B
    Schömig, A
    [J]. AMERICAN JOURNAL OF CARDIOLOGY, 2001, 87 (03) : 332 - +
  • [10] Shear-induced platelet activation and platelet microparticle formation at blood flow conditions as in arteries with a severe stenosis
    Holme, PA
    Orvim, U
    Hamers, MJAG
    Solum, NO
    Brosstad, FR
    Barstad, RM
    Sakariassen, KS
    [J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1997, 17 (04) : 646 - 653