Atherosclerotic-lesion

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). 

Human umbilical vein endothelial cells (HUVEC) express the isoforms ECE-la, -lb, -Id and ECE-2. In these cells, ET-1 is secreted via both a constitutive and a regulated pathway. The ratio of released ET-1 big-ET-1 is 4 1. About 80% of the ET-1 is secreted at the abluminal cell surface of endothelial cells. ECE-isoforms are abundantly expressed on the cell surface of endothelial cells and to a lower level also on vascular smooth muscle cells. In atherosclerotic lesions of vessels, however, ECE expression in smooth muscle cells is upregulated. ECE isoforms expressed in smooth muscle cells contribute significantly to the generation of mature ET in normal and in particular atherosclerotic vessels. 

In addition, ETB receptors are upregulated in vessels with atherosclerotic lesions and in pulmonary vessels of patients with severe pulmonary hypertension. The upregulation can be attributed to increased ETB receptor expression in smooth muscle cells and to ETB receptors expressed on infiltrating macrophages. 

Tissue-Specific Expression. In adult rodents, PPAR.a is expressed in liver, kidney, intestine, heart, skeletal muscle, retina, adrenal gland, and pancreas. In adult human, PPARa is expressed in the liver, heart, kidney, large intestine, skeletal muscle (mostly slow-twitch oxidative type I fibers), and in cells of atherosclerotic lesions (endothelial cells, smooth muscle cells, and monocytes/macrophages). Therefore, regardless of... 

Atherosclerotic lesion l Monocyte recruitment l Progression of atherosclerosis... 

Macrophage/ atherosclerotic lesion Anti-inflammatory effects9 ... 

PPARa Liver, heart, skeletal muscle, atherosclerotic lesions TG- and LDL-C-lowering and HDL-C-raising re-directs excess cholesterol from the peripheral tissues to the liver for excretion into the bile via HDL-C slowed progression of atherosclerosis Fatty acids, eico-sanoids (fatty acids derived from FAS ) Fibrates fenofibrate (Tricor ), genfibrozil (Lopid ) Dyslipidemia... 

PPARy White adipose tissue, atherosclerotic lesions Insulin-sensitizing and glucoselowering re-directs TG from non-adipose tissues and visceral adipose depots for storage in subcutaneous adipose tissue slowed progression of atherosclerosis Fatty acids, eico-sanoids Th iazolid i ned iones pioglitazone (Actos ), rosiglita-zone (Avandia ) Type 2 diabetes, (insulin resistance, metabolic syndrome)... 

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. 

Intermittent claudication is a group of symptoms characterized by pain in the calf muscle of one or both legp, caused by walking and relieved by rest. It is a manifestation of peripheral vascular disease, in which atherosclerotic lesions develop in the femoral artery, diminishing blood supply to the lower leg. Cilostazol is used to treat intermittent claudication. 

The intima of the arterial wall contains hyaluronic acid and chondroitin sulfate, dermatan sulfate, and heparan sulfate proteoglycans. Of these proteoglycans, dermatan sulfate binds plasma low-density lipoproteins. In addition, dermatan sulfate appears to be the major GAG synthesized by arterial smooth muscle cells. Because it is these cells that profiferate in atherosclerotic lesions in arteries, dermatan sulfate may play an important role in development of the atherosclerotic plaque. 

Corti R, Fayad ZA, Fuster V, Worthley SG, Helft G, Chesebro J, Mercuri M, Badimon JJ. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001 104(3) 249. 

The chemical adducts formed by reaction of aldehydes with lysine residues form highly immunogenic epitopes, and antibodies have been prepared specific for malondialdehyde- and 4-hydroxynonenal-conjugated LDL (Gonen et al., 1987 Yla-Herttuala et al., 1989 Jurgens et al., 1990). These antibodies cross-react with material in atherosclerotic lesions but not normal tissue, thus supporting the central role of lipid peroxidation in the patho nesis of atherosclerosis (Yla-Herttuala et al., 1989, 1991). 

LDL extracted from atherosclerotic lesions is in an oxidized state (Yla-Herttuala et al., 1989). 

LDL extracted from human or animal atherosclerotic lesions has been shown to be taken up much fester than plasma LDL by macrophages by means of their scavenger receptors. 

Antibodies that recognize oxidized LDL but not native LDL show positive reactivity in human or animal atherosclerotic lesions, but not the normal arterial wall (Haberland etal., 1988 Palinski et al., 1989, 1990 Rosenfeld etal., 1990). 

Rosenfeld, M.E., Palinski, W., Yla-Herttuala, S., Butler, S. and Witztum, J.L. (1990). Distribution of oxidation-specific lipid oxidation adducts and apo lipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis 10, 336-349. 

Smith, C., Mitchinson, M.A., Aruoma, O. and Halliwell, B. (1992). Stimulation of lipid peroxidation and hydroxyl radical generation by the contents of human atherosclerotic lesions. Biochem. J. 286, 901-905. 

Yla-Herttuala, S., Rosenfeld, M.E., Parthasarathy, S., Glass, C.R., Sigal, E., Witztum, J.L. and Steinberg, D. (1990). Colocalisation of 15-lipoxygenase messenger RNA and protein with epitopes of oxidised low density lipoprotein in macrophage-rich areas of atherosclerotic lesion. Proc. Natl Acad. Sci. USA, 87, 6959-6963. 

The normal arterial wall consists of the intima, media, and adventitia, as illustrated in Fig. 4—3A. The endothelium is located in the intima and consists of a layer of endothelial cells that line the lumen of the artery and form a selective barrier between the vessel wall and blood contents. The internal elastic lamina separates the intima and media, where vascular smooth muscle cells are found. The vascular adventitia comprises the artery s outer layer. Atherosclerotic lesions form in the subendothelial space between the endothelial cells and internal elastic lamina. 

Dysfunction of the endothelium allows lipoproteins, predominantly low-density lipoprotein (LDL) cholesterol, and inflammatory cells, namely monocytes and T lymphocytes, to migrate from the plasma to the sub-endothelial space. Monocyte-derived macrophages ingest lipoproteins to form foam cells. Macrophages also secrete growth factors that promote smooth muscle cell migration from the media to the intima. A fatty streak consists of lipid-laden macrophages and smooth muscle cells and is the earliest type of atherosclerotic lesion. 

Oxidization of LDL-cholesterol is believed to play a significant role in the atherosclerotic process. The antioxidant vitamins, vitamin E and vitamin C, protect LDL cholesterol from oxidation. Evidence from observational and animal studies suggested that increased intake of antioxidant vitamins might inhibit the formation of atherosclerotic lesions and decrease the risk for cardiovascular events.40 However, several large, randomized, prospective studies found no beneficial effect of vitamin E or other antioxidants on cardiovascular outcomes in patients with IHD or IHD risk factors.41,42 Based on this evidence, current guidelines do not recommend supplementation with vitamin E or other antioxidants for the sole purpose of preventing cardiovascular events. 

T cells, NK cells, Recruitment of T cells to endothelial atherosclerotic lesions,... 

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