Abstract 14484: Enhanced Levels of Soluble CD40 Ligand Exacerbate Platelet Aggregation and Thrombus Formation via CD40-Dependent TRAF-2/Rac1/p38 MAPK Signaling Pathway
Objective: We aimed to determine the impact and the signaling mechanisms of sCD40L on platelet function.
Methods and Results: sCD40L strongly enhances activation and aggregation of washed human platelets induced by sub-threshold concentrations of agonists. Human platelets treated with a mutated form of sCD40L that does not bind CD40, and CD40−/− mouse platelets failed to elicit such responses. Furthermore, platelets express multiple members of the Tumor Necrosis Factor Receptor Associated Factor (TRAF) family, among which only TRAF-2 associates with CD40 upon sCD40L stimulation. Noticeably, sCD40L primes resting platelets through activation of the small GTPase Rac1 and its downstream target p38 mitogen activated protein kinase (MAPK), which leads to platelet shape change and actin polymerization. Moreover, in a ferric chloride-induced murine arterial thrombosis model, infusion of sCD40L exacerbates thrombus formation in wild type (WT), but not in CD40−/− mice. This was further associated with increased leukocyte infiltration within the thrombus of sCD40L-treated WT mice.
Conclusions: sCD40L enhances agonist-induced platelet activation and aggregation through CD40-dependant TRAF-2/Rac1/p38 MAPK signaling pathway. Thus, sCD40L is an important platelet primer predisposing platelets to enhanced thrombus formation in response to vascular injury. This may explain in part the link between circulating levels of sCD40L and cardiovascular diseases.
- © 2010 by American Heart Association, Inc.