【作者】 赵凯；

【导师】 李继福； 陈文强；

【作者基本信息】 山东大学 ， 内科学， 2014， 硕士

【摘要】 背景大量研究表明易损斑块的破裂,继发形成血栓是导致急性冠脉综合征(ACS)的主要原因。通过对ACS病人的尸检中发现冠状动脉斑块中存在大量的巨噬细胞、淋巴细胞和肥大细胞,其中巨噬细胞是破裂斑块中细胞的主要成分。斑块纤维帽中侵入的巨噬细胞越多,斑块就越脆弱,这与巨噬细胞分泌的基质金属蛋白酶(MMPs)有关,它可以降解细胞外基质导致纤维帽变薄。同时,在斑块破裂中,巨噬细胞分泌大量的细胞因子IL-1、IL-8、TNFa及细胞粘附分子ICAM-1、VCAM-1、P-选择素等,促进斑块向不稳定方向转化。由于巨噬细胞来源于外周血的单核细胞,因此研究单核细胞与斑块稳定性之间的关系对了解ACS的病理生理有重要意义。自体吞噬是在真核生物中普遍存在的,通过溶酶体系统降解自体多余的或者失去功能的细胞器的过程。研究发现动脉粥样硬化斑块中细胞的变化与自体吞噬有密切关系,本研究主要观察人外周血单核细胞的自体吞噬相关基因蛋白表达和斑块易损性的关系,进而为稳定动脉粥样硬化斑块,减少急性冠脉事件,寻找一个新的治疗靶点。冠状动脉造影术虽然是目前诊断冠心病的“金标准”,但是它只能显示管腔的狭窄情况,而对评价管壁形态、壁厚以及评价斑块稳定性等方面都有很大的局限性。血管内超声是利用有创的导管技术将一带有高频微型超声的探头导入冠状动脉血管腔内进行探测,不仅可以精确地测量管腔直径及横截面积,更重要的是可以评估冠状动脉斑块的稳定性,从而为冠状动脉病变提供更多的信息,因而比冠状动脉造影术有无法比拟的优势。目的1.研究人外周血单核细胞的自体吞噬与冠状动脉粥样硬化斑块易损性的关系。2.探讨稳定型心绞痛患者及急性冠脉综合征患者冠状动脉粥样硬化斑块的血管内超声的特点。方法对40例稳定型心绞痛(SAP)患者及40例急性冠状动脉综合征(ACS)患者行冠状动脉造影和血管内超声检查。应用Western blot技术检测两组患者外周血单核细胞的Beclin-1蛋白、微管相关蛋白1轻链3(MAP1-LC3)及自噬相关蛋白ATG5-ATG12复合物的表达量,应用激光共聚焦显微镜检测自噬特异性蛋白MAP1-LC3在单核细胞内的表达量。结果血管内超声检测SAP组斑块共计62个,其中纤维性斑块占48%(30/62),而ACS组斑块共计71个,其中脂质性斑块占56%(40/71)。ACS患者外周血单核细胞的Beclin-1、MAP1-LC3Ⅱ及ATG5-ATG12的表达量显著低于SAP组(P<0.01)。结论稳定型心绞痛患者的冠状动脉斑块以较稳定的纤维性斑块为主,而急性冠状动脉综合征患者的冠状动脉斑块以易损质软的脂质性斑块为主,且冠心病患者外周血单核细胞的自体吞噬随着冠状动脉粥样硬化斑块的不稳定性的增加而降低,增强外周血单核细胞的自体吞噬可能成为稳定冠状动脉粥样硬化斑块,减少急性冠状动脉事件,降低死亡风险的一个潜在的治疗靶点。更多还原

【Abstract】 BackgroundNumerous studies have indicated that thrombosis secondary to the rupture of vulnerable atherosclerotic plaque is the major cause of acute coronary syndrome (ACS). Autopsies performed on patients with ACS indicates that a large number of macrophages, lymphocytes and mast cells exist in the coronary atherosclerotic plaques. To be more precisely, macrophages are the main components of all the cells in the vulnerable plaques. The more macrophages infiltrate in the fibrous cap, the more vulnerable plaque will be, which results from the matrix metalloproteinases (MMPs) secreted by macrophages that can degrade extracellular matrix leading to the thinning of the fibrous cap. Simultaneously, considerable cytokines such as IL-1、 IL-8、TNFa and various adhesion molecules such as ICAM-1、VCAM-land P-selectin secreted by macrophages promote the plaque to transform into an unstable one. Therefore, an intensive study of functions of peripheral blood monocytes (PBMs) from which macrophages are derived has important significance to understand pathophysiology of ACSAutophagy is a unique and ubiquitous phenomenon in the eukaryocytes, which is defined as a major protein degradation process responsible for the degradation of unnecessary or dysfunctional cellular components via the lysosomal machinery. A great many studies have indicated that autophagy is closely involved in the changes of cells in the atherosclerotic plaques. So, the aim of our study is to elucidate the relationship between autophagy of peripheral blood monocyte (PBM) and the vulnerability of atherosclerotic plaques, furthermore to find a new therapeutic target of stabilizing atherosclerotic plaques and reducing acute coronary events.At present, although coronary angiography (CAG) has been considered as "gold standard" to diagnose coronary heart disease(CHD). Given that it can only display the degree of coronary artery stenosis, there are also many limitations when to evaluate morphology and thickness of coronary wall and the stability of plaques. Intravascular unltrasound(IVUS) is a medical device that combine invasive catheter technology with a high frequency miniature ultrasonic probe. The ultrasound catheter is inserted into coronary artery to detect the lesions, thus it can not only precisely measure the diameter and cross-sectional area of coronary artery, what’s more, it can assess the stability of plaques, which can provide more information about the coronary artery lesions. Therefore IVUS has unparalleled advantages when compared with CAG.Objective1To elucidate the relationship between autophagy of peripheral blood monocyte (PBM) and the vulnerability of atherosclerotic plaques.2To discuss the intravascular ultrasonic features of coronary atherosclerotic plaques in stable angina and ACS patients MethodsForty patients with stable angina pectoris (SAP),40patients with acute coronary syndrome (ACS) compromised the study groups. All of patients underwent coronary angiography (CAG) and intravascular ultrasound (IVUS) examinations. The expression levels of autophagy related protein Beclin-1, microtubule-associated protein1light chain3(MAP1-LC3) and ATG5-ATG12complex in PBM was detected by Western blot. MAP1-LC3(autophagy-specific protein) in the PMB was also examined by laser scanning confocal microscope.ResultsSixty two plaques were detected by IVUS in the SAP patients, which included30fibrous ones, while71plaques were evidenced in the ACS group, which encompassed40lipid ones. The expression levels of Beclin-1, MAP1-LC3and ATG5-ATG12complex in PBM in ACS patients were significantly lower than those in SAP patients (P<0.01).ConclusionThe patients in SAP group had more stable fibrous plaques than those in the ACS group (P<0.01), while the ACS patients had more vulnerable soft lipid ones than those in the SAP group (P<0.01). The autophagy of PBM in patients with coronary heart disease (CHD) decreases with the increasing vulnerability of atherosclerotic plaques. Enhancing the autophagy of PBM may be a potential therapeutic target of stabilizing atherosclerotic plaques, which will reduce the acute coronary events and lower the mortality of patients with CHD.更多还原