Foam-cell Formation

In atherosclerosis, ox-LDL is taken up ultimately by macrophages and smooth muscle cells in the arterial intima. Once loaded with lipid, these cells have a foamy appearance when examined histologically. The accumulation of these so-called foam cells in the artery wall leads to the formation of fatty streaks , which can lead to atheromatous plaque formation and consequent coronary heart disease. 

Therapeutic Interventions in Human Inflammatory Diseases - A Cautionary Note 

Studies have demonstrated reduced serum concentrations of vitamin E in patients with RA (Honkanen etal.. 

1989 Situnayake et al., 1991). No correlation between disease activity and serum vitamin E concentrations was found, but it was su ested that such patients might suffer a reduced antioxidant capacity. However, it is conceivable that a decreased serum antioxidant status is a primary event in the evolution of RA. Recent studies (Heliovaara etal., 1994) have demonstrated that lowered levels of vitamin E, /3-carotene and selenium (required for glutathione peroxidase) together may be a risk fector for subsequent development of RA. 

The effect of prolonged antioxidant therapy in relation to normal physiological processes (for example, redox cycling, cell-cell signalling, transcription factor activation) must be assessed. It is conceivable that the overload of one antioxidant by dietary supplementation (for example, a-tocopherol) may shift the levels of other antioxidants (for example, by decreasing ascorbate and /3-carotene concentrations), with unknown consequences. To assess the potential for lipid-soluble antioxidant treatment in inflammatory diseases such as RA, further investigations into these questions will be needed. 

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Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

KAPLAN M and AVIRAM M (1999) Oxidized low density lipoprotein atherogenic and proinflammatoiy characteristics during macrophage foam cell formation. An inhibitory role for nutritional antioxidants and serum paraoxonase Clinical Chemistry Laboratory Medicine 37,111-9,1. 

Figure 12.7 Schematic diagram showing the role of LDL glycatlon and oxidation in foam-cell formation [adapted from Lyons (1991) and Esterbauer et al. (1992)]. C, cholesterol CE, cholesterol ester.

Binding of Lp(a) to fibronectin, a connective tissue component in atherosclerotic plaques, when considered in adjunct to the former observations, supports the hypothesis that Lp(a), just like LDL, is transported through endothelium, and subsequently immobilized in the arterial intima by binding of matrix components (V6a). The particle then possibly undergoes oxidative modification, is taken up by macrophages, and therefore contributes to foam cell formation and atherogenesis (SI). 

Rashid, I., van Reyk, D. M., and Davies, M. J. (2007). Carnosine and its constituents inhibit glycation of low-densitv lipoproteins that promote foam cell formation in vitro. FEBS Lett. 581,1067-1070. 

Foam-cell formation. Policosanol was administered to 18 Wistar rats with carrageenan-induced granulomas at doses of 2.5 or 25 mg/kg for 20 days. The treatment produced a significant reduction of the foamcell formation in granulomas (extravascular medium) ° h... 

Noa, M., M. C. de la Rosa, and R. Mas. Effect of policosanol on foam-cell formation in carrageenan-induced granulomas in rats. J Pharm Pharmacol 1996 48(3) 306-309. 

Jiang G, Li T, Qiu Y, Rui Y, Chen W, Lou Y (2007) RNA interference for HIF-lalpha inhibits foam cells formation in vitro. Eur J Pharmacol 562(3) 183-190 Jones MR, Zhao Z, Sullivan CP, Schreiber BM, Stone PJ, Toselli PA, Kagan HM, Cohen RA, Ravid K (2004) A3 adenosine receptor deficiency does not influence atherogenesis. J Cell Biochem 92(5) 1034-1043... 

Sterol carrier protein 2 has also been shown to be involved in the intracellular transport and metabolism of cholesterol. Hirai et al. (1994) suggested that sterol carrier protein 2 plays an important role during foam cell formation induced by acetylated LDL and may be an important step in atherosclerosis [142], Lipoproteins can bind lipopolysaccharide and decrease the lipopoly-saccharide-stimulated production of proinflammatory cytokines [142, 143], In addition, lipoprotein entrapment by the extracellular matrix can lead to the progressive oxidation of LDL because of the action of lipoxygenases, reactive oxygen species, peroxynitrite, or myeloperoxidase [144, 145],... 

Hirai A, Kino T, Tokinaga K, Tahara K, Tamura Y, Yoshida S. Regulation of sterol carrier protein 2 (SCP2) gene expression in rat peritoneal macrophages during foam cell formation. A key role for free cholesterol content. J Clin Invest 1994 94 2215-2223. 

Vainio S, Ikonen E. Macrophage cholesterol transport A critical player in foam cell formation. Ann Med 2003 35 146-155. 

Macrophage cholesterol accumulation and foam cell formation are the hallmark of early atherogenesis. Cholesterol accumulation in macrophages can result from impaired balance between external and internal cholesterol sources. LDL, which... 

V. SCREENING FOR INHIBITORS OF MACROPHAGE-DERIVED FOAM CELL FORMATION... 

From this screening work, it is expected that novel microbial products which affect the ACAT-1, TG synthetic pathway or unknown sites responsible for macrophage-derived foam cell formation will be discovered, leading to a new type of anti-atherosclerotic agent and providing a novel target for pharmaceutical intervention. 

I Namatame, H Tomoda, H Arai, K Inoue, S Omura. Complete inhibition of mouse macrophage-derived foam cell formation by triacsin C. J Biochem (Tokyo) 125 317-327, 1999. 

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