Macrophage Differentiation to Foam Cells

Abstract

Foam cell formation from macrophages with subsequent fatty streak formation plays a key role in early atherogenesis. Foam cell formation is thought to be induced by Low Density Lipoproteins (LDL), including oxidized LDL (OxLDL) or minimally modified LDL (mmLDL). Understanding the molecular mechanisms involved in OxLDL-and mmLDL-induced foam cell formation is of fundamental importance for atherosclerosis and cardiovascular disease. The expression of many genes is likely modulated during macrophage transformation into a foam cell. In this mini-review we describe functional consequences of modulation of three groups of genes: Scavenger Receptors (SR-A, CLA-1/SR-BI, CD36, CD68, LOX-1, and SR-PSOX), the PPAR family of nuclear receptors, and a number of genes involved in eicosanoid biosynthesis, including lipoxygenases and leukotriene receptors. Scavenger receptors appear to play a key role in uptake of OxLDL, while mmLDL appears to interact with CD14/TLR4. The regulation of scavenger receptors is, in part, mediated by the PPAR family of nuclear receptors. PPARα and PPARγ agonists, such as thiazolidinediones and fibrates, and PPARδ agonists were tested as atheroprotective drugs and showed some beneficial effects. Eicosanoids are naturally occuring agonists for PPARs. Recent observations indicate a role of the components of the eicosanoid cascade, such as 5-lipoxygenase, 15-lipoxygenase and the leukotriene receptors in foam cell formation. Selective inhibitors of lipoxygenases and leukotriene receptors could be useful in the treatment of atherosclerosis by preventing or reducing foam cell formation.

Age-related Accumulation of Non-heme Ferric and Ferrous Iron in Mouse Ovarian Stroma Visualized by Sensitive Non-heme Iron Histochemistry

“…The characteristics of these cells in aged mouse ovaries were shared with foam cells, which are located in atherosclerotic foci. In foam cells, lipid peroxidation, ceroid accumulation, and autofluorescence have been observed (Lee et al 1998;Shashkin et al 2005;Levy et al 2007). Therefore, we identified the enlarged stromal cells in aged ovaries as macrophages with characteristics of foam cells.…”

The Aryl hydrocarbon receptor is activated by modified low-density lipoprotein

“…Both paraoxonase-1, an HDL-associated enzyme with a well established role in preventing LDL oxidation and cardiovascular disease, and NQO1, a shear-inducible gene that maintains the endogenous lipid-soluble antioxidants ␣-tocopherolhydroquinone and ubiquinol in their reduced and active forms, are directly regulated by AHR activation (12,(32)(33)(34). In addition, exogenous activation of the AHR is sufficient for the induction of the macrophage ''foam cell'' phenotype (35), a lipid-laden form generated by uptake of modified LDL from the sera (36).…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…The chemical modification of these macromolecules, such as oxidization, triggers inflammation with recruitment of monocytes/macrophages which invade the atherosclerotic lesion (Libby, 2002). Foam cells, a peculiar histological marker of the disease, are macrophages which uptake oxidized LDL (Shashkin et al, 2005). In the advanced stage, a fibrous cap, made up by smooth muscle cells and ECM components, surrounds the lesion: its rupture generally triggers the thrombus-mediated life-threatening acute event.…”