Ca(2+) Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis

In atherosclerosis, macrophages in the arterial wall ingest plasma lipoprotein-derived lipids and become lipid-filled foam cells with a limited lifespan. Thus, efficient removal of apoptotic foam cells by efferocytic macrophages is vital to preventing the dying foam cells from forming a large necrotic lipid core, which, otherwise, would render the atherosclerotic plaque vulnerable to rupture and would cause clinical complications. Ca(2+) plays a role in macrophage migration, survival, and foam cell generation. Importantly, in efferocytic macrophages, Ca(2+) induces actin polymerization, thereby promoting the formation of a phagocytic cup necessary for efferocytosis. Moreover, in the efferocytic macrophages, Ca(2+) enhances the secretion of anti-inflammatory cytokines. Various Ca(2+) antagonists have been seminal for the demonstration of the role of Ca(2+) in the multiple steps of efferocytosis by macrophages. Moreover, in vitro and in vivo experiments and clinical investigations have revealed the capability of Ca(2+) antagonists in attenuating the development of atherosclerotic plaques by interfering with the deposition of lipids in macrophages and by reducing plaque calcification. However, the regulation of cellular Ca(2+) fluxes in the processes of efferocytic clearance of apoptotic foam cells and in the extracellular calcification in atherosclerosis remains unknown. Here, we attempted to unravel the molecular links between Ca(2+) and efferocytosis in atherosclerosis and to evaluate cellular Ca(2+) fluxes as potential treatment targets in atherosclerotic cardiovascular diseases.