Atherogenesis

CD4-positive Thl lymphocytes are considered to be the predominant T-cell within human and murine lesions, although both CD8-positive and memory T-cells have also been identified (Jonasson et al, 1986 Stemme 

Mast cells have also been found in signiflcant numbers within atherosclerotic plaques, particularly at sites of plaque rupture (Kovanen et al, 1995). The ability of these cells to secrete matrix-degrading enzymes and their detection in unstable plaques indicates that they may facilitate plaque rupture by damaging the fibrous cap (Kaartinen et al, 1994). 

Other immune cells that have been implicated in atherogenesis are natural killer (NK) T-cells (NKTs) and dendritic cells (DCs). NKTs have a key role in innate immunity and have been detected in human and murine atherosclerotic lesions. LDL receptor (LDLR)-deficient mice depleted of functional NKTs exhibit a reduction in lesion formation, indicating that recruitment of these cells into the vessel wall contributes to the development of atherosclerosis (Whitman et al, 2004). DCs have a crucial role in the initiation of immune responses and are key antigen-presenting cells. Although their role in atherosclerosis is still unclear, they have been identified in the intima of human lesions and at arterial branch points in animal models, where they localize with T-cells and macrophages (Lord and Bobryshev, 2002). 

Unambiguous demonstration of a nonredundant role for individual inflammatory mediators in atherosclerosis requires an in vivo model of the disease that closely mimics the human condition. The generation of small-animal 

Chemokine Cellular source Receptor Target cells 

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Corona.iy Hea.rt Disea.se, A theory for atherogenesis (120) has been developed whereby oxidation of low density Hpoprotein (LDL) within the arterial wall is the critical first step. It has been hypothesized that sufficient intake of antioxidants would prevent oxidation of LDL and reduce development of coronary heart disease (122). Interest in determining the role of antioxidants in blocking LDL oxidation has led to the development of in vitro test systems. 

A major adipokine, molecular weight 28,000 Da (monomeric form), that is secreted only from adipocytes. It exists at high levels in the plasma and has a number of fimctions, including an important role in insulin sensitivity, inflammation (anti-anti-inflammato-ry action) and atherogenesis. Unlike most adipokines, the plasma levels fall in obesity. 

Atherogenesis is the process that leads to changes in the arterial blood vessels, including deposition of cholesterol (atherosclerosis). It is the pathophysiological process behind the vast majority of heart attacks. 

T-cells, representing the adaptive arm of the immune response, also play a critical role in atherogenesis, and enter lesions in response to the chemokines inducible protein-10 (DP-10), monokine induced by DFN-y (MIG), and DFN-inducible T-cell a-chemoattractant (I-TAC), which bind CXCR3 (a chemokine receptor containing two cysteine residues separated by one amino acid), highly expressed by T lymphocytes in the plaque. The... 

Atherosclerotic plaques are lesions in the arterial vessels which arise during the process of atherogenesis. Most cases of acute heart attacks are caused by rupture of an atherosclerotic plaque. 

It is accepted that oxidation of LDL is a key event in endothelial injury and dysfunction. Oxidised LDL (oxLDL) may directly injure the endothelium and trigger the expression of migration and adhesion molecules. Monocytes and lymphocytes interact with oxLDL and the phagocytosis which follows leads to the formation of foam cells, which in turn are associated with the alteration of the expression pattern of growth regulatory molecules, cytokines and pro-inflammatory signals. The proposed role of oxLDL in atherogenesis, based on studies in vitro, is shown in Fig. 2.1. 

Fig. 2.1 Sequence of events in atherogenesis and role of low-density lipoprotein. Native LDL, in the subendothelial space, undergoes progressive oxidation (mmLDL) and activates the expression of MCP-1 and M-CSF in the endothelium (EC). MCP-1 and M-CSF promote the entry and maturation of monocytes to macrophages, which further oxidise LDL (oxLDL). Ox-LDL is specifically recognised by the scavenger receptor of macrophages and, once internalised, formation of foam cells occurs. Both mmLDL and oxLDL induce endothelial dysfunction, associated with changes of the adhesiveness to leukoc)des or platelets and to wall permeability.

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... 

BRAND K, PAGE S, WALLI A K, NEUMAIER D and BAEUERLE P A (1997) Role of nucleat factor kB in atherogenesis Experimental Physiology 82, 297-304. 

Quinn, M.T., Parthasarathy, S., Fong, L.G. and Steinberg, D. (1987). Oxidatively modified low-density lipoproteins a potential role in recruitment and retention of monocyte/ macrophages during atherogenesis. Proc. Nad Acad. Sci. USA 84, 2995-2998. 

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). 

Fig. 9-4). Very low-density lipoprotein particles are released into the circulation where they acquire apolipoprotein E and apolipoprotein C-II from HDL. Very-low density lipoprotein loses its triglyceride content through the interaction with LPL to form VLDL remnant and IDL. Intermediate-density lipoprotein can be cleared from the circulation by hepatic LDL receptors or further converted to LDL (by further depletion of triglycerides) through the action of hepatic lipases (HL). Approximately 50% of IDL is converted to LDL. Low-density lipoprotein particles are cleared from the circulation primarily by hepatic LDL receptors by interaction with apolipoprotein B-100. They can also be taken up by extra-hepatic tissues or enter the arterial wall, contributing to atherogenesis.4,6... 

Properties of Selected Molecules in Atherosclerosis That Affect Atherogenesis and Plaque Formation/Rupture... 

Apo E/CXCR3 double knockout mice on a high-fat diet displayed reduced atherosclerotic lesions during early stages of atherogenesis. 

Growing clinical data also points to the importance of IL-8 in atherogenesis. IL-8 has been found in atheromatous lesions from patients with atherosclerotic disease including carotid artery stenosis (103), CAD (118), abdominal aortic aneurysms (AAA) (103,104,114), and peripheral vascular disease (PVD) (104). Furthermore, studies using plaque explant samples have yielded more direct evidence for IL-8 involvement. Media from cultured AAA tissue induced IL-8-dependent human aortic endothelial cell (HAEC) chemotaxis (122). Homocysteine, implicated as a possible biomarker for CAD, is also capable of inducing IL-8 (123-125) by direct stimulation of endothelial cells (123,124) and monocytes (125). When patients with hyperhomocysteinemia were treated with low-dose folic acid, decreases in homocysteine levels correlated with decreases in IL-8 levels (126). Statins significantly decrease serum levels of IL-6, IL-8, and MCP-1, as well as expression of IL-6, IL-8, and MCP-1 mRNA by peripheral blood monocytes and HUVECs (127). Thus, IL-8 may be an underappreciated factor in the pathogenesis of atherosclerosis. 

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