Atherosclerosis foam-cell formation

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). 

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],... 

Plasma LDL (bad cholesterol) promotes foam cell formation and thus atherosclerosis by a LDLR-independent mechanism apparendy requiring scavenger receptors (see Figure 18-20). 

From the point of view of atherosclerosis, the two most important peripheral trafficking pathways are those to the endoplasmic reticulum (ER), where cholesterol is esterified by acyl-CoA cholesterol acyltransferase (ACAT), and to the plasma membrane, where cholesterol can be transferred to extracellular acceptors in a process known as cholesterol efflux (Chapter 20). The former process leads to the massive CE accumulation seen in foam cells [14-16]. The ACAT reaction utilizes primarily oleoyl-CoA, thus ACAT-derived CE is rich in oleate. In contrast, plasma lipoprotein-CE tends to be rich in linoleate. As expected, therefore, the cholesteryl oleatexholesteryl linoleate ratio in foam cell-rich fatty streak lesions — 1.9 — is relatively high [17]. However, the ratio in advanced lesions is only 1.1, suggesting an increase in lipoprotein-CE in advanced atheromata due to poor cellular uptake of lipoproteins or to defective lysosomal hydrolysis following uptake by lesional cells. Further discussion of the cholesterol esterification pathway appears in Chapter 15, and cholesterol efflux, which is an important mechanism that may prevent or reverse foam cell formation, is covered in Chapter 20. 

LDLs are lipoprotein complexes referred to as "bad cholesterol" because prolonged elevation of LDL levels leads to atherosclerosis. LDLs are the primary transport vehicle for cholesterol synthesized in the liver (See Figure 18.7). Oxidation of LDLs leads to foam cell formation and ultimately an atherosclerotic plaque. The primary apoprotein contained in LDLs is Apo B-100. 

Beauveriolides, cyclodepsipeptides (- de-psipeptides) isolated from the culture broth of fungal Beauveria sp. EO-6979. Beau-verolides I and III contain Ala, Phe, D-Leu (or D-aWo-Ile), and (3S,4S)-3-hydroxy-4-methylactanoic acid. They are inhibitors of macrophage foam cell formation, an activity which may prevent the development of atherosclerosis [I. Namatame et al., J. An-tibiot. 1999, 52, 1 K. Nagai et al., J. Comb. Chem. 2006, 8, 103]. 

Aviram, M., and Rosenblat, M. Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Free Radic. Biol. Med. 2004 37(9) 1304-16. 

LDL is one of the major carriers of cholesterol in circulation. LDL is also known as a bad lipoprotein due to the fact that LDL transports cholesterol and other fat molecules to peripheral tissues (i.e. arterial walls) and plays a crucial role in the development of several cardiovascular-related diseases such as atherosclerosis, stroke, and myoeardial infarction. Oleic acid and lysophosphatidylcholine (Figure 5) are the major constituents of LDL. Oxidized LDL (ox-LDL) is rapidly engulfed by macrophages to induce foam cell formation in the arterial wall [37]. Therefore, ox-LDL is thought to be one of the major contributors to the development of atherosclerosis. Moreover, ox-LDL can enhance coronary vasospasm (vasoconstriction) via induce endotheliinn-dependent vasoconstriction consequently preventing vasodilation and increase the activity of protein kinase C isoforms a and 8 in VSMCs of porcine coronary arteries [38-40]. 

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