Atherosclerosis: Recent developments

Abstract

Atherosclerosis is an inflammatory disease of the large arteries that is the major cause of cardiovascular disease (CVD) and stroke. Here, we review the current understanding of the molecular, cellular, genetic, and environmental contributions to atherosclerosis, from both individual pathway and systems perspectives. We place an emphasis on recent developments, some of which have yielded unexpected biology, including previously unknown heterogeneity of inflammatory and smooth muscle cells in atherosclerotic lesions, roles for senescence and clonal hematopoiesis, and links to the gut microbiome.

Figure 1.. Development of fatty streak lesions.

Lipoproteins enter the intima of sites of shear stress. The lipoproteins then aggregate and become oxidized and otherwise modified, resulting in the activation of the overlying EC to express adhesion and chemotactic molecules for monocytes. The monocytes enter the intima, differentiate to macrophages, and take up modified lipoproteins to give rise to foam cells.

Figure 2.. Development of atherosclerosis lesions.

Macrophages proliferate in response to M-CSF, and foam cells are engulfed by macrophages, a process known as efferocytosis. SMC transform to a proliferative state, migrate to the endothelial region and secrete collagen to give rise to a “fibrous cap”. SMC can also transform to macrophage-like cells that take up lipid to give rise to foam cells. T and B cells also enter the lesion and interact with other cell types to promote or retard lesion development.

Figure 3.. Advanced atherosclerotic lesions and coagulation.

Foam cells and other cells die to give rise to cholesterol-rich necrotic cores. Calcification frequently occurs in the intima or media. Lesions can rupture or EC can erode to stimulate the formation of a thrombus, possibly resulting in an MI or stroke.

Figure 4.. Aging and atherosclerosis.

Three events that often occur in aging are the development of clonal hematopoiesis, senescence, and immuno-aging can promote atherosclerosis. A number of factors associated with atherosclerosis, listed above, can promote hematopoiesis, whereas exercise tends to reduce it. Increased hematopoiesis can in turn lead to leukocytosis and clonal proliferation, which can promote atherosclerosis, forming a vicious cycle. Various cells in lesions can also become senescent (at least in mice). Such cells release a variety of cytokines and immune modulators (senescence associated secreting proteins, SASP) that act inflame or kill nearby cells. Also, some MI macrophages express the ectoenzyme CD88 that can degrade NAD⁺. Recent studies have shown that reduced NAD⁺ levels are associated with a variety of disorders, although atherosclerosis has not yet been studied.

Figure 5.. Genetic factors contributing to atherosclerosis susceptibility.

GWAS studies of CVD have identified about 200 loci that contain candidate genes that fit into several risk categories as indicated, although genes do not as yet fit into any known category. GWAS loci for CVD risk factors, including plasma lipid levels (Graham et al., 2021), hypertension (Cabrera et al., 2019), and diabetes (Mahajan et al., 2018), have each identified hundreds of additional, largely non-overlapping loci. [Figure adapted from (Erdmann et al., 2018)].

Figure 6.. Gene activity across multiple organs is used to infer network models.

Gene-regulatory co-expression networks (GRNs) capturing genetic (inherited) and environmental risk variation organize genes within and across tissues in groups of biological processes and molecular functions that are relevant to the etiology of coronary atherosclerosis. Together GRNs may provide a mechanistic framework in which isolated candidate pathways and genetic risk loci can be understood from a broader molecular multi-organ context. Such framework may be proven important to fulfill the promises of precision medicine. SNPs, single nucleotide polymorphism; SKLM, skeletal muscle; SF, subcutaneous fat; VAF, visceral abdominal fat; AOR, atherosclerotic aortic wall and, MAM, internal mammary artery. Color coding of GRN represents genes from different tissues (red, AOR; orange, MAM; green, SKLM; brown, LIVER; purple, VAF; pink, SF and blue, WHOLE BLOOD) adopted from STARNET.MSSM.EDU (Koplev et al., 2021).