Arterial wall, cholesterol

The oxysterol 7-ketocholesterol is an important COP involved in atherosclerotic lesions and macrophage foam cells (275). There is no direct evidence in humans that COPs contribute to atherogenesis, but it has been found that COP levels are elevated in LDL subfractions that are considered potentially atherogenic (276). In addition, raised levels of 7p-hydroxycholesterol may be associated with an increased risk of atherosclerosis. Arterial injury by COPs causes endothelial dysfunction and arterial wall cholesterol accumulation (277). Even under normocholesterolemic conditions, COPs can cause endothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation. These are all factors believed to be involved in the development of atherosclerotic lesions. The atherogenic potential of COPs has been demonstrated by in vitro cell culture (73, 278), as well as in animal feeding studies (279). Japanese quail fed either purified cholesterol or oxidized cholesterol exhibited greater plasma and liver cholesterol concentrations in association with increased severity of atherosclerotic lesions when fed the oxidized cholesterol (279). 

Atherosclerosis is a degenerative disease which is characterized by cholesterol-containing thickening of arterial walls. Saturated fatty acids, high levels of cholesterol, elevated blood pressure, and elevated serum lipoprotein are well-knowm risk... 

Cholesterol is a principal component of animal cell plasma membranes, and much smaller amounts of cholesterol are found in the membranes of intracellular organelles. The relatively rigid fused ring system of cholesterol and the weakly polar alcohol group at the C-3 position have important consequences for the properties of plasma membranes. Cholesterol is also a component of lipoprotein complexes in the blood, and it is one of the constituents oiplaques that form on arterial walls in atherosclerosis. 

Blake, 1989 Winyard et al., 1989). We suggest that within the inflamed rheumatoid joint (or the artery wall in atherogenesis), the production of ROM and proteases by endothelial cells and/or macrophages may cause the release of copper ions from Cp (see Section 2.2.3.2). It has been reported that Cp is cleaved faster in serum from patients with inflammatory diseases when compared to normal serum (Laurell, 1985). The oxidative modification of LDL by Cp-derived copper ions may explain the observation that increased serum cholesterol values are associated with accelerated atherosclerotic progression in men with high serum copper concentrations (Salonen et al., 1991). 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Atherosclerosis is a wide-spread pathology, manifested chiefly by the deposition of cholesterol in arterial walls, which results in the formation of lipid plaques (atheromas). Lipid plaques are specific foreign bodies around which the connective tissue develops abnormally (this process is called sclerosis). This leads to the cal-cification of the impaired site of a blood vessel. The blood vessels become inelastic and compact, the blood supply through the vessels is impeded, and the plaques may develop into thrombi. 

Besides cholesterol efflux from arterial wall and its role in RCT, additional properties of HDL have been proposed for its protective anti-atherogenic activities. HDL protects vascular function by a number of potential alternative mechanisms, including inhibition of LDL oxidation [8,9], platelet aggregation and coagulation [10], and endothelial monocyte adhesion [11], as well as promotion of endothelial nitric oxide synthase (eNOS) [12], and prostacyclin synthesis [13-15]. The proposed alternate protective mechanisms for HDL are attractive but many of them lack validation under in vivo conditions. 

An old hypothesis is based on the observations of Dahlen et al. (D3), who demonstrated that above a certain concentration in plasma, Lp(a) could bind to glycosaminoglycans in the arterial wall (B12). Colocalization of Lp(a) and fibrin on the arterial wall can lead to oxidative changes in the lipid moiety of Lp(a) and induce the formation of oxidatively modified cholesterol esters, which in turn can influence the interaction of Lp(a) and its receptors on macrophages. This process is promoted by the presence of calcium ions. Cushing (C14), Loscalzo (L22), and Rath (R3) reported a colocalization of undegraded Lp(a) and apo-Bl00 in the extracellular space of the arterial wall. In contrast to LDL, Lp(a) is a substrate for tissue transglutaminase and Factor XUIa and can be altered to products that readily interact with cell surface structures (B21). 

Even during the first or second decade of life, small deposits of lipid, fatty streaks, are often detectable in arterial walls. In a study by R. Ross over half of the children (age 10-14) examined at autopsy had fatty streaks in their arteries. These are the first indications of the entry of fat and cholesterol into macrophages in the subendothelial space of an artery. This initiates a sequence of processes that eventually produces a plaque. A prerequisite for the development of fatty streaks, and hence atherosclerosis, is injury to the endothelial cells fining the arterial wall. Many factors are suspected of causing this, including pollutants. 

One role of high density lipoprotein (HDL) is to collect unesterified cholesterol from cells, including endothelial cells of the artery walls, and return it to the liver where it can not only inhibit cholesterol synthesis but also provide the precursor for bile acid formation. The process is known as reverse cholesterol transfer and its overall effect is to lower the amount of cholesterol in cells and in the blood. Even an excessive intracellular level of cholesterol can be lowered by this reverse transfer process (Figure 22.10). Unfortunately, the level of HDL in the subendothelial space of the arteries is very low, so that this safety valve is not available and all the cholesterol in this space is taken up by the macrophage to form cholesteryl ester. This is then locked within the macrophage (i.e. not available to HDL) and causes damage and then death of the cells, as described above. 

Cholesterol-rich lipoproteins of the LDL type are particularly important in the development of arteriosclerosis, in which the arterial walls are altered in connection with an excess plasma cholesterol level. In terms of dietary physiology, it is important that plant foodstuffs are low in cholesterol. By contrast, animal foods can contain large amounts of cholesterol—particularly butter, egg yolk, meat, liver, and brain. 

Low HDL cholesterol (<35 mg/dL) is an independent risk factor for CHD. HDL appears to antagonize atherogenesis by at least two mechanisms. HDL can mobilize cholesterol from extrahepatic cells (such as arterial wall foam cells) and transport it to the liver for disposal (reverse cholesterol transport) HDL also has antioxidant properties. HDL contains the potent antioxidant enzyme paraoxonase, which may protect LDL lipids from oxidation. Thus, hypertriglyceridemia with... 

High-density lipoproteins (HDL) exert several ant/atherogenic effects. They participate in retrieval of cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL (hypoalphalipoproteinemia) are an independent risk factor for atherosclerotic disease and thus are a target for intervention. 

Cardiovascular heart diseases (CHD) are considered as the clinical expression of advanced atherosclerosis. One of the initial steps in atherogenesis is the oxidative modification of LDL and the uptake of the modified lipoprotein particles by macrophages, which in turn become lipid laden cholesterol-rich cells, so-called foam cells [159]. An accumulation of foam cells in the arterial wall is the first visible sign of atherosclerosis and is termed fatty streak, the precursor to the development of the occlusive plaque [160]. It is well known that oxidation of LDL can be initiated in vitro by incubating isolated LDL particles with cells (macrophages, lymphocytes, smooth muscle cells, or endothelial cells), metal ions (copper or iron), enzymes, oxygen radicals, or UV-light. However less is known about the mechanisms by which... 

High levels of plasma cholesterol do not directly cause heart attacks. Rather, over long periods cholesterol is somehow involved in the progressive development of a disease of the arteries called atherosclerosis. Atherosclerotic plaques are complex lesions in arterial walls that contain abnormal deposits of cholesteryl esters. Precisely how high cholesterol levels in the plasma relate to the development of atherosclerosis is not understood and is a major frontier of medi-... 

Cholesterol is a vital component of the human body. It stabilizes cell membranes and is the precursor of bile acids, vitamin D, and steroid hormones. The body s cells can synthesize cholesterol when needed, but excess cholesterol cannot be broken down and must be excreted from the body through the bile into the small intestine. When imbalances occur, cholesterol can accumulate in the gallbladder promoting gallstone formation. Cholesterol accumulation in the bloodstream (hypercholesterolemia) can cause atherosclerotic plaques to form within artery walls. 

Third, acyl-CoA cholesterol acyltransferase (ACAT) [EC 2.3.1.26], an enzyme that works after the formation of cholesterol, was considered a unique target of inhibition [32], ACAT catalyzes the synthesis of cholesteiyl esters from cholesterol and long-chain fatty acyl-CoA. ACAT plays important roles in the body, for example, in the absorption of dietary cholesterol from the intestines, production of lipoprotein in liver and formation of foam cells from macrophages in arterial walls. Therefore, ACAT inhibition is expected not only to lower plasma cholesterol levels but also to have a direct effect at the arterial wall. A number of synthetic ACAT inhibitors such as ureas, imidazoles, and acyl amides have been developed [33], Several groups have searched for novel ACAT inhibitors... 

We are interested in ACAT-1 inhibitors, which are expected to affect macrophages directly. In the early stages of atherosclerogenesis, macrophages penetrate the intima, efficiently take up modified LDL, store cholesterol and fatty acids as a form of neutral lipids such as CE and TG in the cytosolic lipid droplets, and are converted into foam cells, leading to the development of atherosclerosis in the arterial wall. We established an assay system of lipid droplet formation using intact mouse macrophages and searched for microbial inhibitors of the for-... 

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