冠脉扩张发病机制的研究

发布时间：2018-05-18 10:15

本文选题：冠脉扩张 + 细胞外基质　；参考：《北京协和医学院》2015年博士论文

【摘要】：[研究背景]随着冠脉影像学技术的普及,冠脉扩张(coronary artery ectasia, CAE)越来越多地被人们所认识,其发病率低但绝对人数多,且有类似于冠心病的临床表现,易于发生血栓事件,严重危害患者的健康和生命,然而目前缺乏对其针对性的治疗措施,这主要是因为不清其确切的病因和发病机制。对冠脉扩张发病机制的深入研究,有助于科学地制定治疗策略,从而缓解患者的临床症状和改善长期预后。[研究目的]因为冠脉扩张特征性病理表现为冠脉中层细胞外基质成分的严重损害,我们提出假设：做为机体细胞外基质降解的最终执行者,蛋白酶可能在冠脉扩张细胞外基质的异常代谢过程中发挥着重要作用。本研究拟回答：1)冠脉扩张细胞外基质代谢的特点如何?2)蛋白酶是否和冠脉扩张细胞外基质的异常代谢相关?3)何种来源的蛋白酶参与了冠脉扩张的病程?4)哪些内源性物质能够调控这些酶的作用?本研究期待明确蛋白酶与冠脉扩张的关系,为进一步的研究提供理论基础。[研究方法]因为冠状动脉管壁的主要细胞外基质成分是弹力纤维、Ⅰ和Ⅲ型胶原纤维,本研究首先在血清中检测这些细胞外基质合成和降解的生物标志物,以初步评估冠脉扩张患者细胞外基质代谢的总体情况,同时也研究了其中某些指标的临床诊断价值。进而检测血液中总弹性蛋白酶和总金属基质蛋白酶的活性变化,分析他们与冠脉扩张细胞外基质代谢的相关性,在这个结果的指导下：1)进一步对中性粒细胞来源的蛋白酶及其内源性抑制物做了系统的研究；2)系统筛查了冠脉扩张患者外周血单个核细胞(peripheral blood mononuclear cells, PBMC)相关蛋白酶及其调控分子转录表达谱；3)利用冠脉扩张混合血清模拟体内的病理刺激,培养人脐静脉平滑肌细胞,观察其对蛋白酶表达和细胞外基质代谢的影响,该部分还探讨了细胞因子生长分化因子15 (growth differentiation factor 15, GDF-15)的保护作用。[研究结果]通过对胶原代谢指标系统检测发现：冠脉扩张患者弹性纤维降解增多,总胶原量减少,胶原极性由Ⅲ型为主向Ⅰ型为主转化。这些变化可能与冠状动脉扩张的形成,以及血管的硬化有密切的联系。进一步研究发现,总弹性蛋白酶和总金属质蛋白酶(matrix metalloproteinase, MMP)与弹力纤维降解密切相关。其中弹性纤维的降解产物——可溶性弹力蛋白(soluble elastin, sElastin)有助于冠脉扩张的辅助诊断。在这个基础上开展的实验显示：1)冠脉扩张组的中性粒细胞以一种未知的方式激活,释放出中性粒细胞弹性蛋白酶(human neutrophil elastase, HNE)和组织蛋白酶G (cathepsin G, CG),同时内源性蛋白酶抑制物相应升高来限制它们的过度破坏作用,但这些蛋白酶抑制物同时也抑制了纤溶酶,影响了纤溶系统的功能,理论上增加了冠脉扩张血栓事件的概率。2)系统筛查单个核细胞的蛋白酶及其调控体系的表达谱发现,单个核细胞来源的金属基质蛋白酶MMP1和MMP9,以及单个核细胞来源的细胞因子白细胞介素1α (interleukin-1A, IL1A)、血小板衍化生长因子B(Platelet-derived growth factor B, PDGF-B)、干扰素γ(Interferon gamma, IFNγ)和GDF15,可能都参与到冠脉扩张的疾病进程。3)冠脉扩张混合血清能上调人脐静脉平滑肌细胞MMP1的表达,加入GDF-15后这种上调高能够被抑制,提示GDF-15是可能是一种内源保护性因子。[研究结论]本研究以细胞外基质代谢和蛋白酶解作用为中心开展了一系列的实验,进一步证实冠脉扩张的主要机制是弹力纤维的破坏和胶原总量的减少,其中可溶性弹力蛋白sElastin有望新的辅助诊断指标；参与冠脉扩张的蛋白酶主要有：平滑肌细胞来源的MMP1,单个核细胞来源的MMP1和9,中性粒细胞来源的HNE和CG,同时机体还有一系列内源性的物质来调控蛋白酶的作用,包括数个蛋白酶抑制物和数个细胞因子,其中GDF15有潜力成为治疗冠脉扩张的一种药物。本研究初步证实了蛋白酶与冠脉扩张的密切关系,为后续的深入研究提供了理论基础。
[Abstract]:[background] with the popularization of coronary imaging technology, coronary artery ectasia (CAE) is becoming more and more recognized by people. The incidence of coronary artery disease is low but the absolute number is large, and there are similar clinical manifestations of coronary heart disease. It is easy to have thrombus events and seriously harm the health and life of the patients. However, there is no pertinence to it at present. This is mainly due to the lack of clear etiology and pathogenesis. An in-depth study of the pathogenesis of coronary dilatation helps to scientifically formulate therapeutic strategies to alleviate the clinical symptoms and to improve the long-term prognosis. [Objective] the characteristic pathological manifestations of coronary dilatation are the components of the extracellular matrix of the middle layer of coronary artery. Serious damage, we propose that as the ultimate performer for the degradation of the extracellular matrix of the body, protease may play an important role in the abnormal metabolic process of the extracellular matrix of coronary dilatation. This study is intended to answer: 1) what are the characteristics of the extracellular matrix metabolism in coronary dilatation? 2) whether the protease is extended to the extracellular matrix of the coronary artery Abnormal metabolism related? 3) what is the source of protease involved in the course of coronary dilatation? 4) what endogenous substances can regulate the role of these enzymes? This study expects to clarify the relationship between protease and coronary dilatation and provide a theoretical basis for further research. [research methods] the main extracellular matrix component of the coronary artery wall is a projectile Force fibers, type I and type III collagen fibers. This study first examined the biomarkers of these extracellular matrix synthesis and degradation in serum to evaluate the overall status of the extracellular matrix metabolism in patients with coronary dilatation, and also to study the clinical diagnostic value of some of these indicators. Then, the total elastase and total gold in the blood were detected. The changes in the activity of matrix protease, analysis of their correlation with the metabolism of extracellular matrix of coronary dilatation, under the guidance of this result: 1) further study of neutrophil derived protease and its endogenous inhibitors; 2) systematic screening of peripheral blood mononuclear cells (peripheral blood Mo) in patients with coronary dilatation Nonuclear cells, PBMC) related proteases and their regulatory molecular transcriptional expression profiles; 3) the effects of cultured human umbilical vein smooth muscle cells on the expression of protease and the metabolism of extracellular matrix were observed by using coronary dilatation mixed serum to simulate the pathological stimulation in vivo, and the cytokine growth differentiation factor 15 (growth different) was also discussed. The protective effect of iation factor 15, GDF-15). [results] through the examination of the collagen metabolism index system, it was found that the degradation of elastic fibers in the patients with coronary artery dilatation was increased, the total amount of collagen was reduced, and the collagen polarity was mainly converted from type I to type I. These changes may be associated with the formation of coronary artery dilation and the hardening of blood vessels. Further studies have found that the total elastase and the total metal proteinase (matrix metalloproteinase, MMP) are closely related to the degradation of elastic fibers. The degradation products of the elastic fibers, soluble elastin (soluble elastin, sElastin), are helpful for the auxiliary diagnosis of coronary dilatation. 1) the neutrophils in the coronary dilatation group are activated in an unknown manner, releasing human neutrophil elastase (HNE) and cathepsin G (cathepsin G, CG), while endogenous protease inhibitors increase accordingly to limit their overdestruction, but these inhibitors also inhibit the activity of these protease inhibitors. Plasminase, which affects the function of fibrinolytic system, theoretically increases the probability of coronary dilatation thrombosis (.2), the expression profiles of the protease and its regulatory system of mononuclear cells, the metal matrix protease MMP1 and MMP9 from mononuclear cells, and the cytokine interleukin 1 alpha (Interl) from the single nuclear cell source. Eukin-1A, IL1A), platelet derived growth factor B (Platelet-derived growth factor B, PDGF-B), interferon gamma (Interferon gamma, IFN gamma) and GDF15, may be involved in the progression of coronary dilatation. It is suggested that GDF-15 is probably an endogenous protective factor. [Conclusion] this study conducted a series of experiments centered on extracellular matrix metabolism and proteolysis, and further confirmed that the main mechanism of coronary dilatation is the destruction of elastic fibers and the decrease of total collagen, in which the soluble elastin sElastin is expected to be new. The protease involved in coronary dilatation mainly include MMP1 of smooth muscle cells, MMP1 and 9 of mononuclear cells, HNE and CG derived from neutrophils, and a series of endogenous substances that regulate the role of protease, including several protease inhibitors and several cytokines, of which GDF15 has potential. Force has become a drug for the treatment of coronary dilatation. This study has preliminarily confirmed the close relationship between protease and coronary dilatation, which provides a theoretical basis for further further research.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R541.4

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