Cytokines, inflammatory mediators and atherosclerosis

Atherosclerosis is an inflammatory response of unknown molecular mechanism response to metabolic or physical injury. Hypercholesterolemia is associated with excessive production of oxygen radicals. We postulated that the alteration in the redox-state in the arterial wall and in the endothelial cell (EC) particularly would contribute to the recruitment of monocytes (M) by activating a specific set of redox-sensitive genes. The prototype gene was vascular cell adhesion molecule-1 (VCAM-1) involved in the recruitment of M and the standard stimuli were the cytokines IL-1 and TNFα. EC VCAM gene contains tandem redox-sensitive NF-κB-like enhancer elements in the promoter. Cytokine-induced NF-κB activation and nuclear translocation result from oxidation-sensitive mechanisms as determined by inhibition by intercellular antioxidants such as pyrolidine dithiocarbamate, (PDTC). PDTC inhibits VCAM-1 expression and M binding in response to cytokine stimulation. Validation of the hypothesis that leukocyte recruitment and atherosclerosis development are regulated by redox-sensitive genes has been achieved in cholesterol-fed rabbits. PDTC inhibits aortic cholesterol deposition by up to 80%. These data may contribute to understanding the pathogenesis of atherosclerosis and may define specific molecular targets for new therapeutic approaches.