无创支架取出后支架再狭窄组织内基质金属蛋白酶的活性分布规律、作用机制及调控研究

项目名称： 无创支架取出后支架再狭窄组织内基质金属蛋白酶的活性分布规律、作用机制及调控研究

项目编号： No.81471763

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 肖亮

作者单位： 中国医科大学

项目金额： 72万元

中文摘要： 支架再狭窄（ISR）是严重影响心脑血管疾病中远期预后的科学难题，基质金属蛋白酶（MMP）在平滑肌细胞迁移、增殖及细胞外基质合成、分泌与血管重塑过程中起重要调节作用。由于含金属支架的标本不能进行冰冻切片及石蜡切片，目前ISR组织内MMP活性的时间、空间分布规律及作用机制尚不知晓。申请者采用无创金属支架取出的技术，解除对含金属支架的标本进行全面检测的限制，明确支架置入后血管壁MMP活性强度的时间、空间分布特征规律及相关调节机制、明确MMP在ISR过程中的作用机理，为外源性MMP抑制剂局部释放对ISR过程中MMP活性、平滑肌细胞及细胞外基质代谢进行调控提供理论依据。开辟抑制ISR的新方法、新途径，为新型药物洗脱支架提供技术支持，为解决ISR提供理论依据。

中文关键词： 支架再狭窄；发病机制；基质金属蛋白酶；原位酶谱学；细胞外基质

英文摘要： In stent restenosis (ISR) is still a puzzle deteriorating the long term prognosis of cardiovascular disease. Nowadays, ISR could not be resolved completely by reducing the proliferation of smooth muscle cell (SMC) and promoting endothelialization on stent. Extracellular matrix (ECM) degradation products are potent stimulants for monocytes and fibroblasts, both of which contribute to ECM accumulation after arterial injury. Fibrillar collagen inhibits SMC migration and proliferation, ECM protein synthesis, and expression of matrix receptors, thereby maintaining a quiescent ECM milieu. Matrix metalloproteinase (MMP) also play a critical role in the maladaptive arterial response after injury, including facilitation of cellular migration, activation and release of pro-fibrotic growth factors, induction of apoptosis, inflammation. To restrain the degradation of ECM, interrupt the positive feed-back loop of ECM breakdown products on ECM synthesis, proteolytic inhibitors and adjust the metabolism of ECM and vascular remodeling might be the better route for ISR. Due to frozen section and paraffin section could not be cut in specimen which included metal stent, current researches on ECM and MMP focused on restenosis after balloon dilation, but not after stenting. The blindspot of researches on ISR is about the succession regularity of MMP activity distribution on arterial wall after stent implantation. We hypothesize the succession regularity of MMP activity distribution is increase in media at early-stage, decrease in neointima at medial-stage, increase in adventitia at later-stage after stenting. We have grasped the technique by which metal stent could be taken non-invasively out from frozen vascular specimen. In this research, we will apply in situ zymography methods to explore the temporal succession regularity of MMP activity and the spatial distribution of MMP activity on arterial wall after stent implantation, measure the mRNA level of MMP and tissue inhibitor of MMP, observe the changes of SMC function and metabolism of various composition of ECM and analyze the relations between them and MMP activity.This research might expand a new research area, and supply new objective proof for inhibiting ISR.

英文关键词： In Stent Restenosis;Pathogenesis;Matrix MetalloProteinase;In situ Zymography;Extracellular Matrix