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.

在西方工业国家，动脉粥样硬化占所有死亡原因的 50% 以上。动脉粥样硬化可以解释为炎症过程，即对大量和多种诺克斯引起的损伤的反应。以下是动脉粥样硬化形成的重要发病步骤：内皮功能障碍，修饰的 LDL 胆固醇积累，单核细胞、T 细胞和平滑肌细胞侵入血管内膜以及伴随的分化。除了这些细胞类型外，正在形成的动脉粥样硬化斑块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、细胞周期调节、抗原肽生成、脂质代谢控制和炎症过程调节中发挥关键作用。因此，蛋白酶体似乎是动脉粥样硬化治疗中非常有前途的靶标。本项目的目的是研究动脉粥样硬化形成过程中蛋白酶体亚基表达和活性的调节程度，并确定蛋白酶体系统所产生的影响。在这种情况下，工作计划包括单核细胞和平滑肌细胞的分化模型。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。下一步，我们将在动脉粥样硬化的转基因动物模型中研究这些问题。特别令人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。