Cholesterol, in atherosclerosis

May be harmful following inhalation or ingestion of large quantities, or over prolonged periods of time, owing to the possible involvement of cholesterol in atherosclerosis and gallstones. May be irritant to the eyes. When heated to decomposition, cholesterol emits acrid smoke and irritating fumes. 

The traditional view of atherosclerosis has been simply the deposition and accumulation of cholesterol, other lipids, and cellular debris within the wall of medium to large arteries, resulting in plaque formation and disturbance of blood flow (Fig. 9.2). The role of cholesterol in atherosclerosis is well established and has been elegantly reviewed (Maxfield and Tabas, 2005). It is now... 

Khachadurian, A.K. (1990). Role of cholesterol in atherosclerosis, in Advances in Cholesterol Research, Esfaham M. and Swaney J.B., Eds., The Telford Press, Caldwell, NJ, 385. 

On the other side of the coin, cholesterol has received much attention because of a correlation between its levels in the blood and the disease known as atherosclerosis, or hardening of the arteries (Section 14.1). Although our knowledge of the role played by cholesterol in atherosclerosis is incomplete, it is now considered advisable to reduce the amount of cholesterol in the foods we eat. In addition, reducing the amount of saturated fatty acids in the diet appears to lower cholesterol production by the body. 

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). 

Cholesterol is the central compound in any discussion of steroids. Its name is a combination of the Greek words for bile (chole) and solid (stereos) preceding the characteristic alcohol suffix -ol. It is the most abundant steroid present in humans and the most important one as well because all other steroids arise from it. An average adult has over 200 g of cholesterol it is found in almost all body tissues, with relatively large fflnounts present in the brain and spinal cord and in gallstones. Cholesterol is the chief constituent of the plaque that builds up on the walls of arteries in atherosclerosis. 

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. 

Brown, M.S. and Goldstein, J.L. (1983). Lipxsprotein metabolism in the macrophage implications fiar cholesterol dep>o-sition in atherosclerosis. Ann. Rev. Biochem. 52, 223-261. 

It has been known for many years that elevated levels of serum cholesterol are associated with atherosclerosis, although the cause-effect relationship remains unproven. A rather straightforward therapeutic regimen intended for prevention or arrest of the progress of this disease involves lowering levels of serum cholesterol in the high-risk population. 

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. 

The expression of 15-LOX in atherosclerotic lesions is one of the major causes of LDL oxidative modification during atherosclerosis. To obtain the experimental evidence of a principal role of 15-LOX in atherosclerosis under in vivo conditions, Kuhn et al. [67] studied the structure of oxidized LDL isolated from the aorta of rabbits fed with a cholesterol-rich diet. It was found that specific LOX products were present in early atherosclerotic lesions. On the later stages of atherosclerosis the content of these products diminished while the amount of products originating from nonenzymatic lipid peroxidation increased. It was concluded that arachidonate 15-LOX is of pathophysiological importance at the early stages of atherosclerosis. Folcik et al. [68] demonstrated that 15-LOX contributed to the oxidation of LDL in human atherosclerotic plaques because they observed an increase in the stereospecificity of oxidation in oxidized products. Arachidonate 15-LOX is apparently more active in young human lesions and therefore, may be of pathophysiological importance for earlier atherosclerosis. In advanced human plaques nonenzymatic lipid peroxidation products prevailed [69],... 

A high plasma concentration of LDL (usually measured as LDL-cholesterol) is a risk factor for the development of atheroma whereas a high concentration of HDL is an anti-risk factor for cardiovascular disease (CVD). Fundamental discoveries relating to cholesterol metabolism and the importance of the LDL receptor made by Nobel laureates Joseph Goldstein and Michael Brown led to an understanding of the role of LDL in atherosclerosis. The impact of HDL in reducing CVD risk is often explained by the removal of excess cholesterol from tissues and its return to the liver, a process known as reverse cholesterol transport. However, evidence from research by Gillian Cockerill and others shows that HDL has a fundamental anti-inflammatory role to play in cardioprotection. 

There is a mutant gene that produces an inactive receptor and patients with this mntant snffer from high levels of LDL-cholesterol in their blood. They have a markedly increased risk of developing atherosclerosis and coronary artery disease. 

Atherosclerosis is a condition of the organism characterized by elevated levels of atherogenic lipoproteins in blood plasma, lipid deposits (including cholesterol) in the form of esters inside walls of the arterial system, and it is expressed by a gradual difficulty of blood circulation. The most appropriate name for this disease is lipoproteinemia. Clinically, it is manifested in the form of ischemic heart disease, stroke, abnormal cerebral blood flow, and peripheral ischemia. 

Cholesterol is the prototypic steroid lipid. It was first isolated in 1770 in the 1920s, the German chemists Windaus and Wieland deduced the structure for cholesterol, receiving Nobel Prizes for their work in 1927 and 1928. Cholesterol is important in medicinal chemistry, not only for its role in atherosclerosis, but also because it is an important lipid in membrane structure. 

The plasma lipoproteins are spherical macromolecular complexes of lipids and specific proteins (apolipoproteins or apoproteins). The lipoprotein particles include chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They differ in lipid and protein composition, size, and density (Figure 18.13). Lipoproteins function both to keep their component lipids soluble as they transport them in the plasma, and also to provide an efficient mechanism for transporting their lipid contents to (and from) the tissues. In humans, the transport system is less perfect than in other animals and, as a result, humans experience a yradual deposition of lipid—especially cholesterol—in tissues. This is a potentially life-threat-en ng occurrence when the lipid deposition contributes to plaque formation, causing the narrowing of blood vessels (atherosclerosis). 

Thakur, C. P. and Jha, A. N. 1981. Influence of milk, yoghurt and calcium on cholesterol-induced atherosclerosis in rabbits. Atherosclerosis, 39, 211-215. 

Amyloid cascade hypothesis of Alzheimer s disease. A leading contemporary theory for the biological basis of Alzheimer s disease centers around the formation of beta amyloid. Certainly much of this amyloid destroys cholinergic neurons in the nucleus basalis of Meynert (Fig. 12—11), although the damage becomes more widespread as the disease progresses (Fig. 12-13). Hypothetically, Alzheimer s disease is a disorder in which beta amyloid deposition destroys neurons, in a manner somewhat analogous to that in which the abnormal deposition of cholesterol causes atherosclerosis. Thus,... 

Figs. 12—16 to 12—22) and prevent the progressive course of Alzheimer s disease. Direct inhibition of gene expression for the biosynthesis of these proteins is not currently possible and is currently not a very feasible therapeutic possibility. Perhaps a more realistic therapeutic possibility would be to inhibit the synthesis of beta amyloid, in much the same way that lipid-lowering agents act to inhibit the biosynthesis of cholesterol in order to prevent atherosclerosis. This could be done by means of enzyme inhibitors, such as protease inhibitors, which are at least a theoretical possibility. 

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