The maladaptation of endothelial cells to disturbed flow at arterial bifurcations increases permeability for lipoproteins. Additional injury by chemically modified lipoproteins disrupts the continuous repair of maladapted endothelial cells and triggers intimal macrophage accumulation. Macrophages remove modified lipoproteins from the extracellular space until the cholesterol overload leads to macrophage death and insufficient efferocytosis. This macrophage failure promotes the progression to advanced lesions by formation of a lipid-rich necrotic core, which may rupture and cause myocardial infarction and stroke. In this article, we summarize the fundamental roles of microRNAs (miRNAs) in the regulation of endothelial maladaptation and macrophage failure during atherosclerosis. We describe how miRNAs coordinate the mutual interaction between chronic endothelial repair and endothelial senescence and mechanistically link the regulation of macrophage cholesterol homeostasis with defective efferocytosis. Lastly, we discuss how miRNAs may challenge and extend current theories about atherosclerosis.


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