Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis

Abstract

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.

Warfarin Treatment Is Associated to Increased Internal Carotid Artery Calcification

“…An atherosclerotic lesion in the internal carotid artery is a major cause of cerebral ischemic stroke. Although many elements of the underlying pathological processes of atherosclerosis, e.g., lipid accumulation and the inflammatory component, have been well-characterized in developing atherosclerotic lesions (1), the multifaceted roles of calcification in atherosclerotic lesions are still debated and under investigation (2)(3)(4)(5).…”

The role of calmodulin and calmodulin-dependent protein kinases in the pathogenesis of atherosclerosis

“…Rupture of vulnerable plaques usually occurs in sites close to necrotic cores [ 9 ]. In atherogenesis, macrophages and SMC activation is accompanied by the altered activity or expression of membrane and internal Ca 2+ channels implicating the importance of Ca 2+ signaling in these processes [ 7 12 ].…”

“…In atherosclerotic plaques, macrophages and vascular smooth muscle cells (VSMCs) are two significant components, for which their role is gradually transformed with atherosclerotic lesion evolution. In both cell types, Ca 2+ -dependent signaling is crucial in controlling the inflammation, cell death, proliferation, and migration occurring in atherosclerosis [ 7 8 ]. In this regard, calmodulin (CaM), the most critical calcium sensor in cells, and its target kinases might play a crucial role in bridging Ca 2+ signaling and cellular reactions in response to environmental cues.…”

Potential Mechanisms and Effects of Efferocytosis in Atherosclerosis

“…Ca 2+ was involved in all steps of phagocytosis, including macrophage migration, macrophage survival, actin polymerization, phagocytic cup formation during phagocytosis, intracellular processing of ACs phagocytosis and secretion of anti-inflammatory cytokines. Thus, Ca 2+ based therapy was helpful in the attempt to design personalized and targeted drug treatment for patients with atherosclerotic cardiovascular disease ( 90 ). Crucially, macrophage metabolism controls the efferocytosis contributing to effective clearance of ACs.…”