2016 Russell Ross Memorial Lecture in Vascular Biology: Molecular–Cellular Mechanisms in the Progression of Atherosclerosis

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Abstract

Atherosclerosis is initiated by the subendothelial accumulation of apoB-lipoproteins, which initiates a sterile inflammatory response dominated by monocyte–macrophages but including all classes of innate and adaptive immune cells. These inflammatory cells, together with proliferating smooth muscle cells and extracellular matrix, promote the formation of subendothelial lesions or plaques. In the vast majority of cases, these lesions do not cause serious clinical symptoms, which is due in part to a resolution–repair response that limits tissue damage. However, a deadly minority of lesions progress to the point where they can trigger acute lumenal thrombosis, which may then cause unstable angina, myocardial infarction, sudden cardiac death, or stroke. Many of these clinically dangerous lesions have hallmarks of defective inflammation resolution, including defective clearance of dead cells (efferocytosis), necrosis, a defective scar response, and decreased levels of lipid mediators of the resolution response. Efferocytosis is both an effector arm of the resolution response and an inducer of resolution mediators, and thus its defect in advanced atherosclerosis amplifies plaque progression. Preclinical causation/treatment studies have demonstrated that replacement therapy with exogenously administered resolving mediators can improve lesional efferocytosis and prevent plaque progression. Work in this area has the potential to potentiate the cardiovascular benefits of apoB-lipoprotein–lowering therapy.

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