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

蛋白酶体在动脉粥样硬化病变发展中的作用：蛋白酶体抑制剂在动脉粥样硬化治疗中的可能应用

• 批准号: 5374954
• 负责人: Professor Dr. Karl Stangl
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Kardiologie und Angiologie (CCM)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2005-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5374954?language=en
• 关键词: role; proteasome; development; atherosclerotic; lesions

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.

动脉粥样硬化造成西方工业国家所有死亡原因的不少于50％的责任。在大量和多种诺克斯引起的损伤的反应中，动脉粥样硬化可以解释为一种炎症过程。以下是动脉粥样硬化的基本致病步骤：内皮功能障碍，随着改良的LDL胆固醇的积累，单核细胞的侵袭，T细胞和平滑肌肉细胞侵入血管内膜和伴随分化。发育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调节细胞周期，产生抗原肽，控制脂质代谢以及调节炎症过程中起关键作用。因此，蛋白酶体似乎是动脉粥样硬化治疗的高度有希望的靶标。此处介绍的项目的目的是研究在动脉粥样硬化过程中蛋白酶体在蛋白酶体亚基和活性中调节蛋白酶体的程度，并确定蛋白酶体系统施加的影响。在这种情况下，工作程序CNCOM通过单核细胞和平滑肌肉细胞的分化模型。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。在下一步中，我们将在动脉粥样硬化的trasgenten动物模型中研究这些问题。特别有趣的是，长期抑制蛋白酶体是否会影响动物模型中动脉粥样硬化斑块的发展，以及是否有可能从治疗意义上实现完全发达的斑块的回归。