Macrophages in Atherosclerosis Regression

Abstract

Macrophages play a central role in the development of atherosclerotic cardiovascular disease (ASCVD), which encompasses coronary artery disease, peripheral artery disease, cerebrovascular disease, and aortic atherosclerosis. In each vascular bed, macrophages contribute to the maintenance of the local inflammatory response, propagate plaque development, and promote thrombosis. These central roles, coupled with their plasticity, makes macrophages attractive therapeutic targets in stemming the development of and stabilizing existing atherosclerosis. In the context of ASCVD, classically activated M1 macrophages initiate and sustain inflammation, and alternatively activated M2 macrophages resolve inflammation. However, this classification is now considered an oversimplification, and a greater understanding of plaque macrophage physiology in ASCVD is required to aid in the development of therapeutics to promote ASCVD regression. Reviewed herein are the macrophage phenotypes and molecular regulators characteristic of ASCVD regression, and the current murine models of ASCVD regression.

Keywords: atherosclerosis; coronary artery disease; inflammation; macrophages; thrombosis.

Figure.

Dynamics of macrophage plasticity and trafficking in atherosclerosis. Atherosclerotic lesions are characterized by proinflammatory macrophages which sustain lesion growth by contributing to local and systemic plaque inflammation. Atherosclerosis development and macrophage dysfunction is accelerated during hypercholesterolemia (high LDL-C [lowdensity lipoprotein-cholesterol), and hyperglycemia. Atherogenic lipid-lowering remodels lesions towards a stable phenotype, a process driven mainly by macrophages. Broad changes in the plaque macrophage transcriptome are characteristic of atherosclerosis regression, most commonly distinguished by enrichment of M2-associated transcripts. The dynamic change in plaque macrophage phenotype raises the possibility that inducing of macrophage polarization potential in vivo will represent a viable therapeutic option for atherosclerotic cardiovascular disease regression and suppress residual inflammatory risk.