CLINICAL RESEARCH: EXERCISE EFFECTS
Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization
Mark I. Furman, MD, FACC* ,
Lori A. Krueger, BA, MLT, ART*,
Matthew D. Linden, PhD*,
Marc R. Barnard, MS*,
Andrew L. Frelinger, III, PhD* and
Alan D. Michelson, MD*,*
* Center for Platelet Function Studies, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Division of Cardiovascular Medicine, Departments of Pediatrics and Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Manuscript received July 14, 2003;
revised manuscript received December 16, 2003,
accepted December 23, 2003.
* Reprint requests and correspondence: Dr. Alan D. Michelson, Director, Center for Platelet Function Studies, University of Massachusetts Medical School, Room S5-846, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
michelson{at}platelets.org
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.
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Abbreviations and Acronyms
| | EDTA | = ethylenediaminetetraacetic acid | | ELISA | = enzyme-linked immunosorbent assay | | FITC | = fluorescein isothiocyanate | | GP | = glycoprotein | | HT | = HEPES Tyrode's buffer | | MMPs | = matrix metalloproteinases | | PCI | = percutaneous coronary intervention | | PE | = phycoerythrin | | PerCP | = peridinin chlorophyll protein | | PRP | = platelet-rich plasma | | sCD40L | = soluble CD40 ligand |
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