Atherosclerosis Cholesteryl esters

Kuivenhoven JA, Jukema JW, Zwinder-man AH, de Knijff P, McPherson R, Bruschke AV, et al. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 1998 338 86-93. 

Target genes involved in dmg response can also be involved in disease susceptibility. For example, polymorphisms of the cholesteryl ester transfer protein (CETP) are associated with both coronary atherosclerosis and response to pravastatin [22]. 

Contrary to LDL, high-density lipoproteins (HDL) prevent atherosclerosis, and therefore, their plasma levels inversely correlate with the risk of developing coronary artery disease. HDL antiatherogenic activity is apparently due to the removal of cholesterol from peripheral tissues and its transport to the liver for excretion. In addition, HDL acts as antioxidants, inhibiting copper- or endothelial cell-induced LDL oxidation [180], It was found that HDL lipids are oxidized easier than LDL lipids by peroxyl radicals [181]. HDL also protects LDL by the reduction of cholesteryl ester hydroperoxides to corresponding hydroperoxides. During this process, HDL specific methionine residues in apolipoproteins AI and All are oxidized [182]. 

Cholesterol lowering drugs are indicated for the prevention and treatment of atherosclerosis. There are three families of these dmgs inhibitors of HMG-CoA reductase (statins), inhibitors of cholesterol transport protein, and inhibitors of cholesteryl ester transfer protein (CETP). They are important drugs from an economical point of view. Among them, several are fluorinated. 

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-... 

J Koizumi, H Mabuchi, A Yoshimura, I Michishita, M Takeda, H Itoh, Y Sakai, T Sakai, K Ueda, R Takeda. Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia. Atherosclerosis 58 175-186, 1985. 

K Marotti, CK Castle, TP Boyle, AH Lin, RW Murray, GW Melchior. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature (London) 364 73-75, 1993. 

M Sugano, N Makino, S Sawada, S Otsuka, M Watanabe, H Okamoto, M Kamada, A Mizushima. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J Biol Chem 273 5033-5036, 1998. 

LJ Thomas, MD Picard, DP Miller, CM Honan, H Adari, CD Emmett, HC Marsh, US Ryan, CL Petty, CW Rittershaus. A vaccine to produce anti-cholesteryl ester transfer protein (CETP) antibodies for the prevention/treatment of atherosclerosis. FASEB J 13(Part II) A693, 1999. 

Westerterp M, van der Hoogt CC, de Haan W, Offerman EH, Dallinga-Thie GM, Jukema JW, Havekes LM, Rensen PC. Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE 3-Leiden mice. Arterioscl Thromb Vas Biol 2006 26 2552-9. 

LDL is oxidatively modified when incubated in vitro with three major cellular constituents of the vascular wall endothelial cells [35], vascular smooth muscle cells [35] and macrophages [35-37], The uptake of oxidised LDL occurs via the scavenger-receptor pathway, and expression of scavenger receptors has been demonstrated on macrophages, endothelial cells [38], fibroblasts [39] and smooth muscle cells [39]. Unlike the LDL receptor, expression of the scavenger receptor is not down-regulated by an increase in intracellular cholesterol [40]. Therefore, uptake of Ox-LDL contributes to the accumulation of cholesteryl esters in foam cells of atherosclerotic lesions [40]. Now, the question is Does oxidation of LDL-lipids influence the development of atherosclerosis ... 

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]. 

Helianthus annuus (Asteraceae), Viciafaba (Fabaceae), Phoenix dactylifera (date palm) (Palmae), Rhodophyceae (marine red algae) animal membrane component hyperlipidaemia in many heart attack victims LDL carries cholesteryl esters f LDL -> cholesterol-rich arterial atheromas —> atherosclerosis -> blockage, clots — stroke myocardial infarction (heart attack)... 

When used in conjunction with niacin or niceritol, Sikorski (4) determined that the benzyl amine cholesteryl ester transfer protein inhibiting agent, (III), was effective in treating atherosclerosis. 

The level of intracellular cholesterol is regulated through cholesterol-induced suppression of LDL-receptor synthesis and cholesterol-induced inhibition of cholesterol synthesis. The increased level of intracellular cholesterol that results from LDL uptake has the additional effect of activating acyl-CoA cholesteryl acyl transferase (ACAT) (see below), thereby allowing the storage of excess cholesterol within cells. However, the effect of cholesterol-induced suppression of LDL-receptor synthesis is a decrease in the rate at which LDLs and IDLs are removed from the serum. This can lead to excess circulating levels of cholesterol and cholesteryl esters when the dietary intake of fat and cholesterol is excessive. Excess cholesterol tends to be deposited in the skin and tendons and within the arteries, which can lead to atherosclerosis. 

There is some evidence that atherosclerosis may be caused by an infection of the vascular smooth-muscle cells. Chickens, for example, develop atherosclerosis when infected with the Marek s disease herpesvirus. Herpesvirus infection of arterial smooth-muscle cells has been shown to cause cholesteryl ester accumulation, which is associated with atherosclerosis. 

CETP is a hydrophobic plasma glycoprotein, mainly synthesized in the liver, that possesses the unique ability to facilitate the transfer of cholesteryl ester (CE). CETP circulates in the blood, bound predominantly to HDL. CETP mediates the transfer of cholesteryl esters from HDL to VLDL and LDL in exchange for triglycerides. CETP also promotes the transformation of HDL2 to HDL3, an action that could promote reverse cholesterol transport. CETP inhibition produces an increase in HDL by markedly delaying the catabolism of apoA-I and A-II (129), an action that increases reverse cholesterol transport. These actions of CETP suggest that CETP inhibition could prevent atherosclerosis (130-132). 

Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader 146. DJ, Tall AR. Cholesteryl ester transfer protein a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler. Thromb. 

Inazu I, Koizumi J, Mabuchi H. Cholesteryl ester transfer protein 147. and atherosclerosis. Curr. Opin. Lipidol. 2000 11 389-396. 

Coronary heart disease (CHD) is one of the leading causes of morbidity and mortality in the United States. Hyperlipidemia is a major risk factor for atherosclerosis and CHD. Hyperlipidemia is defined as an elevation in blood cholesterol or triglycerides (TG). Lipids are primarily transported in the body by three major lipoproteins low-density (LDL), very-low-density (VLDL), and high-density lipoproteins (HDL). Cholesteryl esters and TG are carried by the lipoproteins, which vary in size and composition of cholesterol and... 

Another factor that regulates HDL cholesterol levels is the plasma level of cholesteryl ester transfer protein (CETP). CETP, a hydrophobic glycoprotein (M.W. 741,000), facilitates the transfer of cholesteryl esters in HDL and triacylglycerols in LDL and VLDL (see above). In CETP deficiency due to a point mutation (G A) in a splice donor site that prevents normal processing of mRNA, the plasma HDL cholesterol levels of affected individuals are markedly high, with decreased LDL cholesterol. In the affected families, there was no evidence of premature atherosclerosis and, in fact, there was a trend toward longevity. These observations support the role of CETP and the antiatherogenic property of HDL. However, not all factors that elevate HDL levels may be... 

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