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Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization.

Abstract：

OBJECTIVES:The purpose of this study was to examine the effects of glycoprotein (GP) IIb/IIIa antagonists (abciximab, eptifibatide, and tirofiban) and other inhibitors on translocation of CD40L from intraplatelet stores to the platelet surface and on the release of soluble CD40L (sCD40L) from platelets. BACKGROUND:CD40L is a proinflammatory and prothrombotic ligand in the tumor necrosis factor family. METHODS:Platelet surface CD40L was measured by flow cytometry, and sCD40L was measured by enzyme-linked immunosorbent assay. RESULTS:Translocation of CD40L from intraplatelet stores to the platelet surface was not inhibited by GP IIb/IIIa antagonists. However, release of sCD40L from the surface of activated platelets was inhibited by GP IIb/IIIa antagonists in a dose-dependent manner, in concert with inhibition of PAC1 binding to platelets (a surrogate marker for fibrinogen binding). Release of sCD40L from activated platelets was also markedly reduced in Glanzmann platelets (deficient in GP IIb/IIIa). Ethylenediaminetetraacetic acid was an effective inhibitor of sCD40L release, but only when added before platelet activation. Both cytochalasin D (an inhibitor of actin polymerization) and GM6001 (an inhibitor of matrix metalloproteinases [MMPs]) inhibited the release of sCD40L from platelets when added before, as well as 3 min after, platelet activation. However, neither cytochalasin D nor GM6001 affected translocation of CD40L to the platelet surface. CONCLUSIONS:The GP IIb/IIIa antagonists inhibit release of sCD40L from activated platelets. Release of sCD40L from platelets is regulated, at least in part, by GP IIb/IIIa, actin polymerization, and an MMP inhibitor-sensitive pathway. In addition to their well-characterized inhibition of platelet aggregation, GP IIb/IIIa antagonists may obviate the proinflammatory and prothrombotic effects of sCD40L.

journal_name

J Am Coll Cardiol

journal_title

Journal of the American College of Cardiology

authors

Furman MI,Krueger LA,Linden MD,Barnard MR,Frelinger AL 3rd,Michelson AD

doi

10.1016/j.jacc.2003.12.055

subject

Has Abstract

pub_date

2004-06-16 00:00:00

pages

2319-25

issue

12

eissn

0735-1097

issn

1558-3597

pii

S0735109704005868

journal_volume

43

pub_type

杂志文章

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