Atheroma

Other Cardiovascular Agents Effecting Atherosclerosis. A large amount of clinical data is available concerning semm Upid profiles in patients subjected to dmg therapy for other cardiovascular diseases. Atheroma, for example, may be the underlying cause of hypertension and myocardial infarction. There are on the order of 1.5 million heart attacks pet year in the United States (155). 

Calcium Channel Blockers. Because accumulation of calcium is one of the facets of the mote involved process leading to atherosclerosis, it would foUow that the antihypertensive calcium channel blockers might be effective in preventing atheroma. Both verapamil (Table 1) and nifedipine (Table 3) have been shown to stimulate the low density Upoprotein (LDL) receptor (159). This specific receptor-mediated pathway could theoretically improve Upid metaboUsm in the arterial wall, and thereby prove antiatherogenic. These effects have been proven in animals. 

Cells in the atheroma derived from both macrophages and smooth muscle cells that have accumulated modified low-density lipoproteins. Their cytoplasm laden with lipid causes the foamy appearance on microscopy... 

Tissue-Specific Expression. In the adult rodent, PPARy is expressed in brown and white adipose tissue, and at lower levels in intestine, retina, skeletal muscle, and lymphoid organs. In human, PPARy is most abundantly expressed in white adipose tissue and at lower levels in skeletal muscle, the heart, and liver, but not in lymphoid tissues, although PPARy has been identified in macrophages in human atheromas. 

An atherosclerotic lesion consisting of a fibrotic cap surrounding a lipid-rich core. The lesion is the site of inflammation, lipid accumulation, and cell death. Also know as an atheroma. 

Mast cells are present in the normal human heart and even more abundant in diseased hearts [ 16-18,25,47]. Within heart tissue, mast cells he between myocytes and are in close contact with blood vessels. They are also found in the coronary adventitia and in the shoulder regions of coronary atheroma [20, 21], The density of cardiac mast cells is higher in patients with dilated and ischemic cardiomyopathy than in accident victims without cardiovascular diseases [25], Importantly, in some of these conditions there is in situ evidence of mast cell activation [16,34],... 

Kaartinen M, Penttila A, Kovanen PT Accumulation of activated mast cells in the shoulder region of human coronary atheroma, the predilection site of atheromatous rupture. Circulation 1994 90 1669. Kaartinen M, Penttila A. Kovanen PT Mast cells of two types differing in neutral protease composition in the human aortic intima. Demonstration of tryptase- and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas. Arterioscler Thromb 1994 14 966. 

Kaartinen M, Penttila A. Kovanen PT Mast cells in ruptme-prone areas of human coronary atheromas produce and store TNF-a. Circulation 1996 94 2787. 47... 

A number of subtle dysfunctions occur at the cellular and molecular levels in the early stages of disease progression associated with the loss of cellular homeostatic functions of endothelial cells, smooth muscle cells and macrophages which constitute the major cell types in the atheroma environment. These events include the modification of the pattern of gene expression, cell proliferation and apoptosis. 

At cellular level each stage of atheroma development is accompanied by the expression of specific glycoproteins by endothelial cells which mediate the adhesion of monocytes and T-lymphocytes. Their recruitment and migration is triggered by various cytokines released by leukocytes and possibly by smooth muscle cells. Atheroma development continues with the activation of macrophages, which accumulate lipids and become, together with lymphocytes, so-called fatty streaks. The continuous influx, differentiation and proliferation finally leads to more advanced lesion and to the formation of the fibrous plaque. ... 

In conclusion, polyphenols seem to be able to affect the expression of genes involved in the pathogenesis of atherogenesis. Cytokines and adhesion molecules appear to be among the most important genes expressed during the pro-inflammatory situation which precedes the formation of the atheroma, and have also been reported to be affected, at least in part, by phenolics. We... 

Carpenter, K.L.H., Taylor, S.E., Ballantine, J.A., Fussell, B., lialliwell, B. and Mitchinson, M.J. (1993). Lipids and oxidised lipids in human atheroma and normal aorta. Biochim. Biophys. Acta 1167, 121-130. 

Haberland, M.E., Fong, D. and Cheng, L. (1988). Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidaemic rabbits. Science 241, 215-218. 

Overall, and contrary to others (Lyons, 1991), we feel that the weight of scientific evidence indicates that lipid peroxidation is increased in diabetes irrespective of whether complications are present or not. The presence of microangiopathy or severe atheroma is likely to increase the degree of peroxidation even further. 

Circulating lipid peroxides are markedly raised in patients with extensive atheroma... 

Probucol treatment slows progression of atheroma In the Watanabe rabbit... 

However, it remains a valid argument (as in the case of atheroma) that increased oxidative stress may be secondary to (rather than a cause of) endothelial damage in hypertension due to other mechanisms. 

Geng YJ, Holm J, Nygren S, Bruzelius M, Stemme S, Hansson GK. Expression of the macrophage scavenger receptor in atheroma—relationship to immune activation and the T-cell cytokine interferon-gamma. Arterioscler Thromb Vase Biol 1995 15(11) 1995-2002. 

Wang N, Tabas I, Winchester R, Ravalli S, Rabbani LE, Tall A. Interleukin 8 is induced by cholesterol loading of macrophages and expressed by macrophage foam cells in human atheroma. J Biol Chem 1996 271(15) 8837-8842. 

Minami M, Kume N, Shimaoka T, et al. Expression of scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) in human atheroma. Ann N Y Acad Sci 2001 947 373-376. 

Mach F, Sauty A, Iarossi AS, et al. Differential expression of three T lymphocyteactivating CXC chemokines by human atheroma-associated cells. J Clin Invest 1999 104(8) 1041-1050. 

Increased levels in human atherosclerotic lesions. 2. Expressed in atheroma-associated cells. 

Fig. 11.1. Atherogenesis is a persistent inflammatory response that occurs in response to conditions that cause endothelial damage (e.g., hypercholesterolemia and oxLDL). After endothelial cells are activated, they elaborate cytokines, chemokines, and other mediators that recruit mononuclear cells (monocytes and T lymphocytes) to extravasate into the vessel wall where they are activated and release additional proinflammatory factors. Macrophages are able to take up oxLDL via scavenger receptors causing them to differentiate into foam cells and form a fatty streak that progresses to an atheroma with a necrotic lipid core and a fibrous cap. Chemokines can lead to weakening of the fibrous cap and eventual plaque rupture leading to thrombosis and occlusion of the involved vessel.

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