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

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.

Keywords: apoptosis; atherosclerosis; efferocytosis; inflammation; macrophages; necrosis; resolution.

Figure

Progression of atherosclerosis. Subendothelially retained apoB LPs incite a sterile inflammatory response, but in the majority of lesions, as depicted on the left, enough of a resolution response is mounted to prevent the formation of clinically dangerous plaques. Highlighted here is a positive-feedback cycle between efferocytosis and pro-resolving mediators, leading to the prevention of cell necrosis and a favorable pro-resolving:inflammatory mediator balance; and a scarring response in which intimal SMCs promote the formation of a protective fibrous cap. A small minority of these lesions progress, as depicted on the right. These lesions have persistent and amplified inflammatory stimuli (apoB LPs) and defective efferocytosis, which then promotes cell necrosis, an imbalance in the pro-resolving:inflammatory mediator balance, and thinning of the fibrous cap. This progression of events can lead to plaque rupture, acute lumenal thrombosis, and tissue ischemia or infarction (bottom image). Not depicted here is another type of advanced, clinically dangerous atherosclerotic lesion that is characterized by endothelial erosion rather than plaque necrosis. Whether a defective resolution response contributes to the formation of this type of plaque remains to be investigated.