Mechanisms of foam cell formation in atherosclerosis

Abstract

Low-density lipoprotein (LDL) and cholesterol homeostasis in the peripheral blood is maintained by specialized cells, such as macrophages. Macrophages express a variety of scavenger receptors (SR) that interact with lipoproteins, including SR-A1, CD36, and lectin-like oxLDL receptor-1 (LOX-1). These cells also have several cholesterol transporters, including ATP-binding cassette transporter ABCA1, ABCG1, and SR-BI, that are involved in reverse cholesterol transport. Lipids internalized by phagocytosis are transported to late endosomes/lysosomes, where lysosomal acid lipase (LAL) digests cholesteryl esters releasing free cholesterol. Free cholesterol in turn is processed by acetyl-CoA acetyltransferase (ACAT1), an enzyme that transforms cholesterol to cholesteryl esters. The endoplasmic reticulum serves as a depot for maintaining newly synthesized cholesteryl esters that can be processed by neutral cholesterol ester hydrolase (NCEH), which generates free cholesterol that can exit via cholesterol transporters. In atherosclerosis, pro-inflammatory stimuli upregulate expression of scavenger receptors, especially LOX-1, and downregulate expression of cholesterol transporters. ACAT1 is also increased, while NCEH expression is reduced. This results in deposition of free and esterified cholesterol in macrophages and generation of foam cells. Moreover, other cell types, such as endothelial (ECs) and vascular smooth muscle cells (VSMCs), can also become foam cells. In this review, we discuss known pathways of foam cell formation in atherosclerosis.

Aging‐ and vascular‐related pathologies

“…Once adherent to the vascular surface, monocytes enter the intima and differentiate into macrophages that take up modified LDL to form foam cells. 34 A recent study elegantly demonstrated that senescent foam cells with reduced telomere length are vital for plaque buildup, and in later stages, plaque remodeling and rupture. 35 These senescent cells show heightened profiles of proatherogenic and proteolytic factors, including IL-1α, TNFα, MMP-3, MMP12, MMP13, MCP-1, and VCAM-1.…”

CTRP13 inhibits atherosclerosis via autophagy‐lysosome‐dependent degradation of CD36

“…Atherosclerosis and its complications rank as the leading cause of cardiovascular mortality with the hallmarks of lipid deposition and inflammatory response. The oxidative modification of sequestered lipoproteins triggers the migration of circulating monocytes into the subendothelial space and differentiation into macrophages, which rapidly engulf modified LDL and transform into foam-cell formation (1)(2)(3). Macrophages that accumulate in atherosclerotic plaques seem to have a diminished capacity to migrate.…”

SCAPknockdown in vascular smooth muscle cells alleviates atherosclerosis plaque formationviaup‐regulating autophagy inApoE−/−mice

“…VSMCs are a source of foam cells, which are the defining pathologic characteristic of atherosclerotic plaques (22). Intracellular lipid homeostasis reflects a balance of cholesterol uptake, endogenous synthesis, and cholesterol export.…”