尿激酶型纤溶酶原激活物受体（uPAR）与易损斑块的关系研究
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摘要
背景冠状动脉内不稳定粥样斑块,即易损斑块的纤维帽破裂、局部血栓形成是引起急性冠脉综合征(ACS)的主要发病机制。目前关于易损斑块形成的机理尚未完全阐明,多数学者认为斑块纤维帽的破裂是由于纤维帽细胞外基质(ECM)降解多于合成的结果。尿激酶型纤溶酶激活物受体(uPAR)是一种细胞膜糖蛋白受体,当与尿激酶纤溶酶激活物结合后参与多种细胞外基质的降解。基质金属蛋白酶-9(MMP-9)是另一种与细胞外基质降解相关的物质,它与uPAR激活之间是否存在关系值得研究。
目的本研究旨在研究uPAR和MMP-9在易损斑块形成中的联系,并探索能否用uPAR表达状况来预测易损斑块。
方法动物实验：小鼠粥样斑块通过免疫组化方法,观察uPAR和MMP-9在斑块中的分布,探索二者有无联系；临床试验：收集急性冠脉综合症、稳定性心绞痛、高脂血症和体检正常四组人群,通过流式细胞仪检测外周血单核细胞上uPAR表达,观察其在四组人群的差异；对于ACS组人群,连续测定经皮冠脉介入(PCI)术前、后外周血中uPAR水平,观察其变化情况。
结果动物实验：uPAR在各期斑块中均有表达,但晚期易损斑块表达量明显增加,尤其在脂质池、斑块肩部、和破裂部位均有表达；MMP-9在早期斑块中基本不表达,而在中、晚期斑块则表达增加,且分布位置与uPAR一致。临床试验：1、ACS组术前外周血uPAR水平,显著高于其余三组；体检正常组显著低于其余三组；稳定型心绞痛组与高脂血症组没有明显差异；2、血脂升高的程度与外周血uPAR水平呈明显正相关；3、ACS患者PCI术后前3天外周血uPAR水平均较术前升高,3天以后,外周血uPAR水平逐渐降低。4、通过流式细胞检测发现,ACS患者外周血单核细胞体积和颗粒度均偏大者,其表达uPAR的荧光强度高于细胞体积和颗粒度均偏小者。
结论uPAR在粥样硬化早期发生中开始起作用,uPAR与MMP-9可能共同参与了易损斑块的形成。uPAR可能作为冠心病临床不稳定的指标之一。
Background Acute coronary syndrome (ACS) is mainly caused by the fibrous cap rupture of vulnerable plaque and then local thrombosis. Recently, the mechanism of the formation of vulnerable plaque has not yet fully understood. Most researchers believe that rupture of the fibrous cap is due to extracellular matrix (ECM) more degradation than synthesis. Urokinase plasminogen activator receptor (uPAR), a cellular membrane glycoprotein receptor, participates in a variety of extracellular matrix degradation, after combined with urokinase plasminogen activator(uPA). Matrix metalloproteinase-9(MMP-9) is another protease associated with extracellular matrix degradation, it's not clear the relationship between MMP-9and uPAR, which is the target of our research。
Objectives The purpose was to study the relationship between uPAR and MMP-9during the formation of vulnerable plaque and to explore whether using of the level of uPAR of monocytes in peripheral vessels to predict the vulnerable plaque.
Methods Animal experiment:immunohistochemistry was employed to detect the expression of uPAR as well as its association with MMP-9in different types of plaque, using the mice model of atherogenesis. Clinical Trials: Clinically acute coronary syndrome、stable angina、normal people with hyperlipidemia and normal subjects were enrolled in the study. The proportion of peripheral monocytes expressing uPAR was surveyed by flow cytometer, to observe differences among the four groups. For the ACS group, uPAR levels in peripheral monocytes were sequential detected before and after percutaneous coronary intervention (PCI) to observe the changes.
Results Animal experiment:uPAR was detected in all stages of plaque, but the expression significantly increased in later vulnerable plaque, especially in the lipid pool, plaque shoulders, and rupture sites. MMP-9was almost undetectable in early plaques. however, the expression gradually increased from the middle to late plaques, and its distribution was similar with uPAR. Clinical Trials:1、ACS preoperative uPAR levels in peripheral monocytes was significantly higher than the other three groups; physical normal group was significantly lower than the other three groups, SAP group was no significant different with hyperlipidemic group.2、Hyperlipidemia might be a critical pair of factors activating uPAR expression.3、For ACS patients, uPAR levels during the first3days after PCI were significantly higher than the preoperative levels.3days later, uPAR levels gradually decreased.4、For ACS patients, the expression of uPAR with peripheral mononuclear cells, whose size and particle size were both larger, was higher than those ones, whose cell size and particle size are both smaller, especially in the fluorescence intensity.
Conclusions uPAR play a role in very early stage of the pathogenesis of atherosclerosis. uPAR and MMP-9might be involved in the formation of vulnerable plaque. uPAR may be as one of clinical indicators of unstable stable angina.
目的本研究旨在研究uPAR和MMP-9在易损斑块形成中的联系,并探索能否用uPAR表达状况来预测易损斑块。
方法动物实验：小鼠粥样斑块通过免疫组化方法,观察uPAR和MMP-9在斑块中的分布,探索二者有无联系；临床试验：收集急性冠脉综合症、稳定性心绞痛、高脂血症和体检正常四组人群,通过流式细胞仪检测外周血单核细胞上uPAR表达,观察其在四组人群的差异；对于ACS组人群,连续测定经皮冠脉介入(PCI)术前、后外周血中uPAR水平,观察其变化情况。
结果动物实验：uPAR在各期斑块中均有表达,但晚期易损斑块表达量明显增加,尤其在脂质池、斑块肩部、和破裂部位均有表达；MMP-9在早期斑块中基本不表达,而在中、晚期斑块则表达增加,且分布位置与uPAR一致。临床试验：1、ACS组术前外周血uPAR水平,显著高于其余三组；体检正常组显著低于其余三组；稳定型心绞痛组与高脂血症组没有明显差异；2、血脂升高的程度与外周血uPAR水平呈明显正相关；3、ACS患者PCI术后前3天外周血uPAR水平均较术前升高,3天以后,外周血uPAR水平逐渐降低。4、通过流式细胞检测发现,ACS患者外周血单核细胞体积和颗粒度均偏大者,其表达uPAR的荧光强度高于细胞体积和颗粒度均偏小者。
结论uPAR在粥样硬化早期发生中开始起作用,uPAR与MMP-9可能共同参与了易损斑块的形成。uPAR可能作为冠心病临床不稳定的指标之一。
Background Acute coronary syndrome (ACS) is mainly caused by the fibrous cap rupture of vulnerable plaque and then local thrombosis. Recently, the mechanism of the formation of vulnerable plaque has not yet fully understood. Most researchers believe that rupture of the fibrous cap is due to extracellular matrix (ECM) more degradation than synthesis. Urokinase plasminogen activator receptor (uPAR), a cellular membrane glycoprotein receptor, participates in a variety of extracellular matrix degradation, after combined with urokinase plasminogen activator(uPA). Matrix metalloproteinase-9(MMP-9) is another protease associated with extracellular matrix degradation, it's not clear the relationship between MMP-9and uPAR, which is the target of our research。
Objectives The purpose was to study the relationship between uPAR and MMP-9during the formation of vulnerable plaque and to explore whether using of the level of uPAR of monocytes in peripheral vessels to predict the vulnerable plaque.
Methods Animal experiment:immunohistochemistry was employed to detect the expression of uPAR as well as its association with MMP-9in different types of plaque, using the mice model of atherogenesis. Clinical Trials: Clinically acute coronary syndrome、stable angina、normal people with hyperlipidemia and normal subjects were enrolled in the study. The proportion of peripheral monocytes expressing uPAR was surveyed by flow cytometer, to observe differences among the four groups. For the ACS group, uPAR levels in peripheral monocytes were sequential detected before and after percutaneous coronary intervention (PCI) to observe the changes.
Results Animal experiment:uPAR was detected in all stages of plaque, but the expression significantly increased in later vulnerable plaque, especially in the lipid pool, plaque shoulders, and rupture sites. MMP-9was almost undetectable in early plaques. however, the expression gradually increased from the middle to late plaques, and its distribution was similar with uPAR. Clinical Trials:1、ACS preoperative uPAR levels in peripheral monocytes was significantly higher than the other three groups; physical normal group was significantly lower than the other three groups, SAP group was no significant different with hyperlipidemic group.2、Hyperlipidemia might be a critical pair of factors activating uPAR expression.3、For ACS patients, uPAR levels during the first3days after PCI were significantly higher than the preoperative levels.3days later, uPAR levels gradually decreased.4、For ACS patients, the expression of uPAR with peripheral mononuclear cells, whose size and particle size were both larger, was higher than those ones, whose cell size and particle size are both smaller, especially in the fluorescence intensity.
Conclusions uPAR play a role in very early stage of the pathogenesis of atherosclerosis. uPAR and MMP-9might be involved in the formation of vulnerable plaque. uPAR may be as one of clinical indicators of unstable stable angina.
引文
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2. Glass CK., Witztum JL.. Atherosclerosis. the road ahead. Cell.2001; 104:503-516.
3. Shireman PK., Pearce WH.. Endothelial cell function:biologic and physiologic functions in health and disease. AJR Am J Roentgenol.1996; 166:7-13.
4. Ross R.. Atherosclerosis--an inflammatory disease. N Engl J Med.1999; 340:115-126.
5. Saksela 0.. Cell-associated plasminogen activation:regulation and physiological functions. Cell Biol.1988; 4:93-126.
6. Christ G.. Plasmin activation system in restenosis:Role in pathogenesis and clinical prediction. J. Thrombosis and Thrombolysis.1999;7:277-285.
7. Martin BS., Padro T., Schwaenen C, et al. Overexpression of urokinase receptor and cell surface urokinase-type plasminogen activator in the human vessel wall with different types of atherosclerotic lesions. Blood Coagulation and Fibrinolysis.2004;15:383-391.
8. Raghunath P. Plasminogen activator system in human coronary atherosclerosis. Arterioscler Thromb Vasc Biol.1995;15(9):1432-1443.
9. Abboud RT, Fera T, Johal S, et al. Effect of smoking on plasma neutrophil elastase levels. J Lab Clin Med.1986:108:294-300.
10.陈未,陈连凤,朱文玲等.冠心病危险因素促使外周血单核细胞高表达尿激酶型纤溶酶原激活物受体的研究.中华心血管病杂志.2007;35：159-163.
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