sCD40L调控斑块内胶原代谢网络的机制研究及干预策略

项目名称： sCD40L调控斑块内胶原代谢网络的机制研究及干预策略

项目编号： No.81200211

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 李莉

作者单位： 山东大学

项目金额： 23万元

中文摘要： 动脉粥样硬化（AS）斑块内胶原的代谢平衡已成为近年来研究斑块不稳定发生机制的热点之一。胶原代谢平衡主要通过胶原合成与降解来调节，MMPs可降解细胞外基质导致斑块不稳定，P4Hα1则与胶原合成密切相关。研究表明多种炎症因子通过影响胶原代谢而导致斑块不稳定。sCD40L是AS的炎症免疫调节中的重要的细胞因子，研究发现，sCD40L可通过调节MMPs在斑块中表达来影响AS斑块的稳定性，但sCD40L与P4Hα1关系目前尚未见报道。我们前期研究发现抑制P4Hα1会使胶原产生减少，而P4Hα1基因的过表达则和胶原产生过量有关，研究还发现抗炎因子过表达能显著增加斑块及HASMCs内P4Hα1表达及胶原含量。但sCD40L能否同时调控MMPs、P4Hα1表达目前尚不明确。因此，本研究拟从体内和体外两个水平观察sCD40L与MMPs、P4Hα1表达的关系及可能的作用机制，旨在为防治AS带来新的治疗靶点。

中文关键词： 动脉粥样硬化；可溶性CD40L配体；基质金属蛋白酶；脯氨酰4-羟化酶；瑞舒伐他汀

英文摘要： In recent years, theories about the role of extracellular matrix (ECM) in the pathogenesis of atherosclerosis have been developed. ECM components, especially collagen-is thought to be important in the progression of atherosclerosis and plaque rupture. The stability of plaques is maintained by a balanced ECM metabolism of production and degradation. Degradation of extracellular matrix by matrix metalloproteinases (MMPs) can lead to the progression of atherosclerosis and plaque rupture. MMP-2 and MMP-9 have been identified in human atherosclerotic lesions, and the enhanced expression of MMP-9 at the shoulders of these lesions has been linked to plaque rupture. Collagen biosynthesis involves a number of posttranslational modifications of procollagens and proteolytic conversion to collagens. The synthesis of all known types of collagen depends on prolyl 4-hydroxylase (P4H). P4H is composed of α and ? subunits; the α subunit is rate limiting and essential for collagen maturation and secretion. Inhibition of P4H produces unstable collagen associated with decreased collagen level. Various interleukins may participate in ECM metabolism by decreasing the activity of the type I isoenzyme of P4H. At present, many groups have studied the degradation of collagen, but it is not very clear about the relationship between a bala

英文关键词： atherosclerosis；sCD40L；matrix metalloproteinases；prolyl 4-hydroxylase；rosuvastatin