Atherosclerosis cytokine expression

Recent evidence suggests that atherosclerosis is a chronic inflammatory process. The recruitment of mononuclear leukocytes and formation of intimal macrophage-rich lesions at specific sites of the arterial tree are key events in atherogenesis. Alterations of chemotactic and adhesive properties of the endothelium play an important role in this process [82]. Quercetin has been reported to inhibit the expression in glomerular cells of monocyte chemoattractant protein-1 (MCP-1) [83] a potent chemoattractant for circulating monocytes. Red wine reduced MCP-1 mRNA and protein expression in abdominal aorta of cholesterol fed rabbits after balloon injury and this effect was associated with a reduced neointimal hyperplasia [84]. The antioxidant-mediated inhibition of nuclear factor k B (NFkB) and the subsequent non selective reduction of cytokine transcription have been suggested to be responsible for these effects [83]. Additionally, quercetin downregulated both phorbol 12-myristate 13-acetate (PMA)- and tumour necrosis factor-a (TNFa)-induced intercellular adhesion molecule-1 (ICAM-1) expression in human endothelial cells [86]. 

It is important to note that an elevated and/or altered plasma lipid level is only one of a wide range of risk factors that contribute to the clinical manifestations of cardiovascular disease in humans (Lusis, 2000). Consequently, in some studies, the reduced incidence of atherosclerosis in animals fed CLA was not accompanied by an improvement in the plasma lipid profile during the CLA feeding phase (Wilson et al, 2000). Reasons for these effects are not understood fully. However, atherosclerosis can also be considered as a chronic inflammatory disease (Libby, 2002) and several important anti-inflammatory effects have been associated with the use of RA these include a reduction in the expression of COX-2, PGE2, reduced release of nitric oxide, a decreased production of pro-inflammatory cytokines, and PPARy activation (Urquhart et al, 2002 Yu et al, 2002 Toomey et al, 2003). 

Oxidised LDL in the artery wall initiates a series of reactions designed to repair the damage it causes. Initial damage triggers an inflammatory response. Monocytes enter the artery waU from the bloodstream, with platelets adhering to the area of insult. This may be promoted by induction of factors such as vascular ceU adhesion molecule 1 (VCAM-1), a cell-surface sialoglycoprotein that is expressed by cytokine-activated endothelium. This membrane protein mediates leukocyte-endothelial cell adhesion and signal transduction, and may play a role in the development of atherosclerosis and rheumatoid arthritis. 

Figure 3 Adipokine expression and secretion by adipose tissue in insulin-resistant, obese subjects. Obesity results in adipose tissue inflammation with macrophage infiltration. This result leads to 1) a decrease in adiponectin, which si an anti-inflammatory adipokine, that is positively correlated with insulin sensitivity and plays a protective role on the vasculature and 2) an increase in inflammatory cytokines (TNFa, IL-6, and resistin) which causes insulin resistance, inflammation, and atherosclerosis. From Reference 47 with permission.

An interesting link between inflammation, atherosclerosis and NOS has been recently described [60]. In this study, the stimulation of iNOS through endothelin resulted in an increased production of NO, along with a concurrent suppression of the expression of vascular cell adhesion molecule-1 (VCAM-1). It is well known that a hallmark of inflammation is the adhesion of leukocytes to post-capillary venular endothelium and the consequent infiltration of leukocytes into the tissue interstitium. NO, by modulating cytokine-induced ECAM expression through the regulatory factor kB, may here act as antiinflammatory, keeping under control the very basic mechanisms of the atherosclerotic lesion. 

Risk and protective factors of atherosclerosis influence VCAM-1 expression [10,19]. A possible relation between VC AM expression and oxidized LDL was established when an important component of this modified lipoprotein, lysophosphatidylcholine, was shown to stimulate VCAM expression and increase adhesion of monocytes on endothelium in cell cultures [10,18,19]. Modified LDL and its constituents augment c)4 okine-activated VCAM-1 expression in human vascular endothelial cells [10,20]. In contrast, HDL inhibits cytokine-induced expression of endothelial cell adhesion molecules [10,21]. -3 Fatty acids have been found to decrease mRNA levels and surface expression of VCAM-1 in endothelial cells [10,22]. Aspirin inhibits induction of mRNA and cell surface expression of VCAM-1 by TNF-a and thereby inhibits monocyte adhesion on stimulated endothelial cells [10,23]. In contrast to ICAM-1, E-selectin, and P-selectin, endothelial VCAM-1 can mediate leukocyte adhesion via its sole interaction with the integrins 4P1 or 4P7 [10]. 

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