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

在西方工业国家，动脉粥样硬化是造成不少于50%死亡的原因。动脉粥样硬化可以被解释为一个炎症过程的意义上说，对损伤的反应所造成的大量和各种各样的毒素。以下是动脉粥样硬化形成中的基本发病步骤：内皮功能障碍，伴随修饰的LDL胆固醇的积累，单核细胞、T细胞和平滑肌细胞侵入血管内膜并伴随分化。发展中的动脉粥样硬化斑块除了这些细胞类型外，还含有细胞外基质蛋白、脂蛋白和细胞碎片。蛋白酶体在细胞分化和细胞周期的调节、抗原肽的产生、脂质代谢的控制和炎症过程的调节中起关键作用。因此，蛋白酶体是治疗动脉粥样硬化的一个非常有前途的靶点。本研究的目的是研究在动脉粥样硬化形成过程中蛋白酶体亚基的表达和活性受到调节的程度，并确定蛋白酶体系统的影响。在这种情况下，工作计划cncompasses分化模型与单核细胞和平滑肌细胞。在这些模型中，我们将分析蛋白酶体的表达和活性，以及蛋白酶体抑制对分化的影响。下一步，我们将在转基因动脉粥样硬化动物模型中研究这些问题。特别感兴趣的是蛋白酶体的长期抑制是否会影响动物模型中动脉粥样硬化斑块的发展，以及是否有可能在治疗意义上实现完全发展的斑块的消退。

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.