CD40 ligand linked to enhanced thrombus formation
MedWire News: Soluble CD40 ligand (sCD40L) is a platelet primer that encourages improved thrombus formation following vascular injury, Canadian research shows.
"This study provides novel evidence for the regulation of platelet function by sCD40L and may partly explain the link between levels of circulating sCD40L and the occurrence of cardiovascular complications," remark Yahye Mehri (Montreal Heart Institute, Quebec) and colleagues.
They explain that "CD40L is a thromboinflammatory molecule that predicts cardiovascular events."
To determine the impact of sCD40L on platelets and the signaling mechanisms by which both molecules interact , Mehri and team carried out a series of experiments in vitro and in vivo.
They found that in vitro, sCD40L strongly enhanced platelet activation and aggregation by interacting with its receptor CD40. In contrast, when treated with a non-CD40 binding form of sCD40L, human platelets and CD40-deficient mouse platelets failed to elicit such responses.
Further investigation showed that sCD40L acted on platelets via activation of the small GTPase Rac1 and its downstream target p38 mitogen-activated protein kinase, which ultimately led to platelet shape change and actin polymerization.
To explore the relationship between sCD40L and thrombosis, the researchers infused the protein into wild-type (WT) and CD40-deficient mice before vascular injury. They subsequently assessed thrombus formation, which occurred significantly faster and to a greater degree (95% vs 30% occlusion 15 minutes post-injury) in sCD40L-treated WT mice compared with untreated controls. No significant difference in thrombosis was observed between treated and untreated CD40 deficient mice, however.
Similarly, leukocyte infiltration was significantly increased post-thrombosis in WT but not in CD40-deficient mice that received sCD40L.
"These results establish a direct in vivo correlation between circulating levels of sCD40L and arterial thrombosis, while highlighting the requirement of the CD40 receptor in this process," write Mehri and co-authors in the journal Arteriosclerosis, Thrombosis and Vascular Biology.
They conclude: "The CD40L/CD40 axis may ultimately represent a therapeutic target in the treatment of thromboinflammatory diseases."
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By Laura Dean