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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2428.)
© 2005 American Heart Association, Inc.

Thrombosis

CD40 Ligand Influences Platelet Release of Reactive Oxygen Intermediates

Subrata Chakrabarti; Sonia Varghese; Olga Vitseva; Kahraman Tanriverdi; Jane E. Freedman

From the Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Mass.

Correspondence to Subrata Chakrabarti, Boston University School of Medicine, 715 Albany St, W507, Boston, MA 02118. E-mail subrata{at}bu.edu

Objective— Soluble CD40 ligand (sCD40L) has been recently implicated in the pathogenesis of atherosclerosis. Elevated levels of sCD40L in acute coronary syndrome patients suggests enhanced platelet function; however, the exact mechanism by which this occurs is unknown. In this study, we examined the effect of sCD40L on platelet function and reactive oxygen and nitrogen species (RONS) generation.

Methods and Results— Platelet stimulation in the presence of recombinant sCD40L (rsCD40L) led to enhanced generation of RONS as measured by DCFHDA oxidation and confocal microscopy. Incubation with rsCD40L led to enhanced platelet P-selectin expression, aggregation, and platelet-leukocyte conjugation. Platelets isolated from CD40L-deficient mice had decreased agonist-induced NO release as compared with wild-type mice. Incubation of platelets with rsCD40L enhanced stimulation-induced p38 MAP kinase and Akt phosphorylation.

Conclusion— Soluble CD40L enhances platelet activation, aggregation, and platelet-leukocyte conjugation, as well as increases stimulation-induced platelet release of RONS through activation of Akt and p38 MAP kinase signaling pathways. These data suggest that sCD40L regulates platelet-dependent inflammatory and thrombotic responses that contribute to the pathogenesis of atherothrombosis.

The role of sCD40L in platelet function and RONS formation was examined. Soluble CD40L enhances platelet activation, aggregation, and platelet-leukocyte conjugation, as well as increases stimulation-induced platelet release of RONS through activation of Akt and p38 MAP kinase signaling pathways. sCD40L influences platelet-dependent thrombotic and inflammatory responses contributing to atherothrombosis.

Key Words: platelets • reactive oxygen species • CD40 ligand • fluorescence

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