Macrophage-derived foam cells

The accumulation of apo(a) in the aorta wall and in saphenous vein bypass grafts in relation to Lp(a) levels was recently demonstrated (C14, R3). Subsequently, the preferential deposition of extracellular apo(a) in atherosclerotic lesions of aortic and coronary artery tissue, in conjunction with the intracellular localization of apo(a) in macrophage-derived foam cells, has been the focus of a number of studies (N6, P7, S34, S35, W17). These careful studies also demonstrated the avid binding of Lp(a) to extracellular matrix components and the colocalization of fibrin and apo(a) in atheromatous lesions (N8, W16). 

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. 

A monoclonal antibody (mAb5A3) has also been developed for protein-bound THP.364 Using it, THP adduct has been found in macrophage-derived foam cells in human atherosclerotic lesions. 

The antiatherosclerotic effect of proanthocyanidin-rich grape seed extracts was examined in cholesterol-fed rabbits. The proanthocyanidin-rich extracts [0.1% and 1% in diets (w/w)] did not change the serum lipid profile, but reduced the level of the cholesteryl ester hydroperoxides (ChE-OOH) induced by 2,2/-azo-bis(2-amidinopropane-dihydrochloride (AAPH), the aortic malonaldehyde (MDA) content and severe atherosclerosis. The immuno-histochemical analysis revealed a decrease in the number of the oxidized LDL-positive macrophage-derived foam cells on the atherosclerotic lesions of the aorta in the rabbits fed the proanthocyanidin-rich extract. When the proanthocyanidin-rich extract was administered orally to the rats, proantho-cyanidin was detected in the plasma. In an in vitro experiment using human plasma, the addition of the proanthocyanidin-rich extract to the plasma inhibited the oxidation of cholesteryl linoleate in the LDL, but not in the LDL isolated after the plasma and the extract were incubated in advance. From these results, proanthocyanidins of the major polyphenols in red wine might trap ROSs in the plasma and interstitial fluid of the arterial wall, and consequently display antiatherosclerotic activity by inhibiting the oxidation of the LDL [92]. 

Free radical damage is considered to be a causative factor in the development of cancer and inflammatory and chronic diseases. Therefore, free radical scavenging molecules (antioxidants) may play a beneficial role in these conditions. With repect to CVD, the oxidation of low-density lipoprotein (LDL) is believed to be a critical process in the development of atherosclerosis (Berliner et al., 1995 Navab et al., 1995). The presence of oxidized LDL in the intima of an artery leads to the production of macrophage-derived foam cells, the main cell type present in fatty streaks that are believed to be the earliest lesion of atherosclerosis (Fuster, 1994). Therefore, the use of antioxidants as dietary supplements to protect against LDL oxidation may reduce both the development and progression of atherosclerosis (Gey, 1995). 

Lipton, B., Parthasarathy, S., Ord, V., Clinton, S., Libby, P, Rosenfeld M. Components of the protein fraction of oxidized low density lipoprotein stimulates interleukin-la production by rabbit arterial macrophage-derived foam cells. J. Lipid Res. 1995 36 2232--12. 

Liu LK, Lee HJ, Shih YW, Chyau CC, Wang CJ (2008) Mulberry anthocyanin extracts inhibit LDL oxidation and macrophage-derived foam cell formation induced by oxidative LDL. J Food Sci 73 H113-H121... 

Dentan C, Lesnik P, Chapman MJ, Ninio E. Phagocytic activation induces formation of platelet-activating factor in human monocyte-deiived macrophages and in macrophage-derived foam cells. Relevance to the inflammatory reaction in atherogenesis. EurJBiochem 19% 236 48-55. 

Acyl-CoA cholesterol acyl transferase (ACAT) catalyzes the intracellular formation of cholesteryl esters (CE) in all mammalian cells. It has been implicated as a key enzyme involved in cholesterol absorption, very low density lipoprotein secretion, and the formation of lipid-laden macrophages. The accumulation of CE in macrophage-derived foam cells is characteristic of the early step in the development of atherosclerosis. ACAT inhibitors reduced TC levels without affecting HDL-C. This can be attributed to decreased intestinal cholesterol absorption based on binding to bile acid (Turley SD. and Herndon MW. 1994)... 

---