Platelet-derived CD40L: the switch-hitting player of cardiovascular disease.

Abstract

Studies focusing on cellular and molecular mechanisms that regulate atherosclerosis have fed scientific journals for decades, nearly as long as it takes an atherosclerotic plaque to grow, rupture, and eventually induce vascular occlusive events. See p 981 Three closely linked lines of research have now merged. In the 1980s, concepts crystallized on the role of lipids (eg, oxidized LDL, elevated cholesterol) in the genesis of atherosclerotic plaque. In the 1990s, use of antiplatelet agents proved that platelet aggregation caused thrombotic ischemic events resulting from the rupture of plaques in advanced lesions and from the vascular injuries inflicted by percutaneous interventions (PCI). Now, atherosclerosis is recognized as an inflammation-mediated disease involving multiple interactions between leukocytes, cells of the vessel wall, and platelets. Indeed, recent studies of predictors of cardiovascular risk rank markers of inflammation (eg, high-sensitive C-reactive protein) as comparable to markers of cholesterol (eg, total cholesterol/HDL cholesterol). Emerging data suggest that CD40L may be at the heart of the atherosclerotic process. What makes CD40L so unique? Its localization and its multifunctionality (Figure 1). CD40L is a surprisingly abundant protein in platelets and may have roles in the inflammatory aspects of atherosclerotic lesion progression, thrombosis, and now, as implied by the work of Urbich et al1 in this issue of Circulation , in restenosis. Figure 1. Three functions of sCD40L released from platelets during thrombosis. sCD40L is released from platelet-rich thrombi and contributes to various steps in atherosclerotic lesion progression: (1) Inflammation. sCD40L induces the production and release of proinflammatory cytokines from vascular cells and matrix metalloproteinases from resident cells in the atheroma. (2) Thrombosis. sCD40L stabilizes platelet-rich thrombi. (3) Restenosis. sCD40L inhibits the reendothelialization of the injured vessel, potentially leading to the activation and proliferation of smooth muscle cells. CD40L is a trimeric, transmembrane protein of the tumor necrosis …