The role of the proteasome in the development of atherosclerotic lesions: possible application of proteasome inhibitors in the therapy of atherosclerosis

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Atherosclerosis is held responsible for no less than 50% of all causes of death in Western industrial nations. Atherogenesis can be interpreted as an inflammatory process in the sense of a response to injury caused by a great number and variety of noxae. The following are essential pathogenetic steps in atherogenesis: endothelial dysfunction with accumulation of modified LDL cholesterol, invasion of monocytes, T-cells, and smooth-muscle cells into the vascular intima and concomitant differentiation. The developing atherosclerotic plaque contains, in addition to these cell types, extracellular matrix proteins, lipoproteins, and cell debris. The proteasome plays a key role in cellular differentiation and in the regulation of the cell cycle, in generation of antigenic peptides, in control of lipid metabolism, and in regulation of inflammatory processes. Therefore, the proteasome appears to be a highly promising target in the therapy of atherosclerosis. The objective of the project presented here is to investigate the extent to which the proteasome is regulated in the expression of proteasomal subunits and activity in the process of atherogenesis, and to determine the influence exerted by the proteasomal system. In this context, the program of work cncompasses differentiation models with monocytes and smooth-muscle cells. In these models we will analyze proteasomal expression and activity, as well as the influence of proteasomal inhibition on differentiation. In the next step, we will investigate these questions in a trasgenetic animal model of atherosclerosis. Of particular interest will be whether long-term inhibition of the proteasome will influence the development of atherosclerotic plaques in the animal model, and whether it is possible to achieve regression, in a therapeutic sense, of fully developed plaques.