Macrophage death in atherosclerosis: potential role in calcification

Cell death is an important aspect of atherosclerotic plaque development. Insufficient efferocytosis of death cells by phagocytic macrophages leads to the buildup of a necrotic core that impacts stability of the plaque. Furthermore, in the presence of calcium and phosphate, apoptotic bodies resulting from death cells can act as nucleation sites for the formation of calcium phosphate crystals, mostly in the form of hydroxyapatite, which leads to calcification of the atherosclerotic plaque, further impacting plaque stability. Excessive uptake of cholesterol-loaded oxidized LDL particles by macrophages present in atherosclerotic plaques leads to foam cell formation, which not only reduces their efferocytosis capacity, but also can induce apoptosis in these cells. The resulting apoptotic bodies can contribute to calcification of the atherosclerotic plaque. Moreover, other forms of macrophage cell death, such as pyroptosis, necroptosis, parthanatos, and ferroptosis can also contribute by similar mechanisms to plaque calcification. This review focuses on macrophage death in atherosclerosis, and its potential role in calcification. Reducing macrophage cell death and/or increasing their efferocytosis capacity could be a novel therapeutic strategy to reduce the formation of a necrotic core and calcification and thereby improving atherosclerotic plaque stability.

Automated summary

Cell death plays a vital role in atherosclerotic plaque development. Insufficient clearance of dead cells by macrophages leads to necrotic core formation and plaque instability. Additionally, apoptotic bodies resulting from dead cells can act as nucleation sites for calcium phosphate crystal formation, leading to plaque calcification. Excessive uptake of cholesterol-loaded oxidized LDL by macrophages results in foam cell formation, which reduces efferocytosis capacity and induces cell apoptosis, further contributing to plaque calcification. Other forms of macrophage cell death, such as pyroptosis, necroptosis, parthanatos, and ferroptosis, can also promote plaque calcification. This review highlights the role of macrophage death in atherosclerosis and its potential impact on calcification. Targeting macrophage cell death and enhancing efferocytosis capacity could be a promising therapeutic strategy to improve plaque stability by reducing necrotic core formation and calcification.