Macrophage differentiation to foam cells.
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. PPARalpha and PPARgamma agonists, such as thiazolidinediones and fibrates, and PPARdelta 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.
Shashkin
Pavel
P
University of Virginia Health System, Cardiovascular Research Center, MR5 Bldg. - Rm. 1013, P.O. Box 801 394, Charlottesville, VA 22908, USA. shashkp@ccf.org
Dragulev
Bojan
B
Ley
Klaus
K
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D015777:Eicosanoids / Q000502:physiology; D005487:Foam Cells / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000502:physiology; D008264:Macrophages / Q000502:physiology*
D015777:Eicosanoids; D008077:Lipoproteins, LDL; D002784:Cholesterol