The role of CD40/CD40 ligand system in the pathogenesis of atherosclerosis

Abstract

Increasing evidence shows that the cells associated with atherogenesis (platelets, endothelial and smooth muscle cells, fibroblasts, monocytes, macrophages and T lymphocytes) express proinflammatory pathways of CD40 signalling. Activation of platelets CD40/CD40L system and its counterpart CD40 receptors on vascular cell surface induces the expression of various adhesion molecules, cytokines, chemokines, growth factors, matrix metalloproteinases and reactive oxygen species, the substances which are responsible for plaque formation, destabilisation and rupture. Disturbed laminar blood flow (low wall shear stress) can mediate CD40/CD40L system signalling by increasing the residence time of the interaction between platelets and endothelium.
Experimental studies provide considerable data indicating that interruption of CD40 signalling significantly inhibits the progression of established atheroma and altered plaque composition for a lipid-poor collagen-rich stable plaque phenotype. Recent data suggest different aspects of CD40/CD40L system activation in the context of risk factors (hypercholesterolaemia, diabetes mellitus, obesity and cigarette smoking) link them into the pro-inflammatory and prothrombotic milieu, aggravating the atherosclerotic process. Activation of the CD40/CD40L system plays a pivotal role in acute coronary syndromes as well as acute cerebral ischaemia. After percutaneous coronary intervention the risk of restenosis increases with high levels of plasma-soluble CD40L (sCD40L). In apparently healthy women sCD40L concentration has been recognised as an independent risk factor of the first acute coronary event. Clopidogrel, aspirin, statins and some oral hypoglycaemic agents share common anti-inflammatory properties including inhibition of CD40/CD40L intercellular signalling. To prevent plaque progression, destabilisation and thrombotic complications, anti-platelet treatment strategy should be focused on inhibition of platelet activation instead of on response to platelet aggregation.