尿激酶型纤溶酶原激活物受体（uPAR）与动脉粥样硬化之间的相关性研究
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摘要
背景：纤溶系统不仅介导纤维蛋白的溶解,而且还参与体内很多病理生理过程,例如细胞迁移、组织重塑以及炎症反应等。尿激酶型纤溶酶原激活物受体(uPAR)作为纤溶系统中一个重要成员,是一个具有多种重要生理功能的分子。它可以与细胞外及细胞膜上特定分子结合,如尿激酶型纤溶酶原激活物(uPA)、玻璃体粘连蛋白(VN)、整合素等,从而发挥重要的生理学功能。作为一个糖基化磷脂酰肌醇锚定于细胞膜上的受体,uPAR余了可以激活细胞周围蛋白水解,还参与细胞黏附、细胞增殖和趋化等过程,这些生物学功能贯穿于动脉粥样硬化发生演变的始终。越来越多证据表明,uPAR在动脉粥样硬化的发生发展中发挥着重要作用,但其中确切的机制尚未明确。
目的：利用动脉粥样硬化斑块的动物模型,检测斑块发展各阶段外周血单核细胞及斑块内部uPAR的表达水平,探讨动脉粥样硬化发生发展与uPAR表达之间的相关性。
方法：39只纯合C57BL/6雄性apoE-/-小鼠喂养至8周龄时被随机分成3个对照组(以Ⅰ、Ⅱ、Ⅲ组表示,每组6只小鼠)和3个实验组(以Ⅳ、Ⅴ、Ⅵ组表示,每组7只小鼠),分别喂以高脂饮食和普通饮食。于喂养第10周处死Ⅰ、Ⅳ组,第13周处死Ⅱ、Ⅴ组,第16周处死Ⅲ、Ⅵ组,分别测量每个动物的体重及腹部脂肪重量,留取外周血标本、心脏及主动脉标本(包括头臂动脉)。外周血标本通过流式细胞仪测定单核细胞中uPAR阳性细胞的比例。动脉标本通过HE染色寻找并计数各期斑块,通过免疫荧光及免疫组化的方法测定斑块内部单核巨噬细胞及泡沫细胞中uPAR的表达水平。
结果：首先,本研究成功建立了动脉粥样硬化斑块的小鼠模型,在三个实验组动物身上均出现了明确的斑块,而三个对照组动物身上却没有发现任何斑块。其次,在实验组动物中,随着高脂饮食喂养周数的增加,动物的体重及腹部脂肪含量也逐渐增加,各组间存在显著性差异(p<0.05)；与此同时,动脉斑块病变的严重程度也逐渐加重,第10周动物以早期病变为主,如脂纹,而第16周动物则晚期病变如纤维斑块和钙化斑块为主。第三,对外周血单核细胞uPAR阳性率测定结果显示：实验组动物的阳性率明显高于对照组,而在3个实验组内部,随着高脂喂养周数增加,外周血单核细胞uPAR阳性率也逐渐升高,3组间存在显著差异(p<0.01)。斑块内部uPAR表达量随着病变严重程度的加重而升高。第四,对斑块内部uPAR阳性的单核巨噬细胞和泡沫细胞数量进行测定的结果显示：钙化斑块>纤维斑块>早期病变如脂纹>正常动脉管壁(p<0.05),而在纤维斑块或钙化斑块内部：脂质核心或坏死核心>纤维帽(p<0.05)。
结论：利用纯合apoE-/-C57BL雄性小鼠饲以高脂饮食能够成功建立动脉粥样硬化动物模型。随着斑块的发生及发展,小鼠外周血单核细胞uPAR表达阳性率逐渐升高。斑块内部uPAR表达量随着病变严重程度的加重而升高。所有这些结果均证实uPAR与动脉粥样硬化发生发展之间密切相关,为进一步深入研究uPAR在粥样硬化形成中的作用和机制打下了基础。
Background Fibrinolytic system exerts pleiotropic functions over the course of many physiologic and pathological processes, including cell migration, tissue remodeling and inflammation response. The urokinase-type-plasminogen-activator receptor (uPAR) is a key molecular of this system and can bind both extracellular moleculars and cell membrane moleculars, such as urokinase type plasminogen activator (uPA), vitronectin (VN), and integrins and so on. As a glycosylphosphatidylinositol-linked receptor, uPAR not only plays a key role in cell suface-associated proteolysis, but also involved in several processes not related to plasminogen activation including cellular adhesion, proliferation and chemotaxis, all of which are fundamental processes in atherogenesis. More and more studies had implicated that uPAR plays an important role in the development of atherogenesis, but the exact mechanism still remains to be elucidated.
Objectives Using the animal model of atherogenesis, we determined the levels of uPAR of monocytes or macrophages both in peripheral vessels and in atherosclerotic plaques with different degrees of atherosclerotic lesions. The purpose is to evaluate the relationship between atherogenesis and the expression of uPAR.
Methods39Male apolipoprotein E-knockout mice were randomised into6groups from the age of8weeks, including3control groups (Group1,11and III,6mice in each group) and3experimental groups (Group IV, V and VI,7mice in each group). The animals of experimental groups were fed a high-fat, cholesterol-enriched diet, while the control groups were fed a normal diet. Animals were euthanized at3-week intervals between10and16weeks of feeding, with1experimental group and1control group were euthanized each time. During dissection, the body weight of each animal were recorded, the peripheral blood and cardiovascular pathological samples were collected. The proportion of peripheral monocytes expressing uPAR was surveyed by flow cytometer. For cardiovascular pathological samples, HE staining was used to search and count the number of atherosclerotic plaques with different degrees of atherosclerotic lesions. Immunohistochemistry and immunofluorescence were employed to detect the expression of uPAR protein as well as its association with macrophages and SMC in different type of plaque.
Results First, this study built the animal model of atherogenesis successfully. The animals of experimental groups were all found different type of atherosclerotic plaques, while none of the animals in control groups was found any atherosclerotic plaques. Second, as the weeks went on, body weight of the animals in experimental groups increased rapidly. There was significant difference between these groups (p<0.05). At the same time, the degrees of atherosclerotic lesions were progressing weekly. More early lesions could be seen in animals with10weeks of high-fat diet, while more severe lesions could be found in animals with16weeks of high-fat diet. Third, Surface expression of uPAR on peripheral monocytes was significantly higher in animals with high-fat diet, compared with that in animals with normal diet (p<0.03). Even more, among the animals with high-fat diet, the expression of uPAR on peripheral monocytes increased as the fed weeks went on. There was significant difference between there experimental groups (p<0.01). Fourth, the level of uPAR in different type of plaques were detected and the results are showed as follows:calcified plaques(CP)> fibrous plaques(FP)> early lesions(EL)> normal areas(NA)(p<0.05); the core of CP or FP> the cap of CP or FP.
Conclusions Our study confirmed that male apolipoprotein E-knockout mice fed with a high-fat, cholesterol-enriched diet can build the animal model of atherogenesis successfully. With the development of atherosclerotic plaques, the expression of uPAR on mouse peripheral monocytes increased gradually. With the degree of atherosclerotic plaques developing, the level of uPAR in atherosclerotic plaques increased gradually. All these data confirm that the overexpression of uPAR both in peripheral monocytes and in advanced atherosclerotic lesions contributes to atherosclerotic plaques' development. This study provided new knowledge of monocyte/macrophage's atherogenic role by uPAR, and further investigation was required to elucidate its mechanism and the possibility of clinical application.
目的：利用动脉粥样硬化斑块的动物模型,检测斑块发展各阶段外周血单核细胞及斑块内部uPAR的表达水平,探讨动脉粥样硬化发生发展与uPAR表达之间的相关性。
方法：39只纯合C57BL/6雄性apoE-/-小鼠喂养至8周龄时被随机分成3个对照组(以Ⅰ、Ⅱ、Ⅲ组表示,每组6只小鼠)和3个实验组(以Ⅳ、Ⅴ、Ⅵ组表示,每组7只小鼠),分别喂以高脂饮食和普通饮食。于喂养第10周处死Ⅰ、Ⅳ组,第13周处死Ⅱ、Ⅴ组,第16周处死Ⅲ、Ⅵ组,分别测量每个动物的体重及腹部脂肪重量,留取外周血标本、心脏及主动脉标本(包括头臂动脉)。外周血标本通过流式细胞仪测定单核细胞中uPAR阳性细胞的比例。动脉标本通过HE染色寻找并计数各期斑块,通过免疫荧光及免疫组化的方法测定斑块内部单核巨噬细胞及泡沫细胞中uPAR的表达水平。
结果：首先,本研究成功建立了动脉粥样硬化斑块的小鼠模型,在三个实验组动物身上均出现了明确的斑块,而三个对照组动物身上却没有发现任何斑块。其次,在实验组动物中,随着高脂饮食喂养周数的增加,动物的体重及腹部脂肪含量也逐渐增加,各组间存在显著性差异(p<0.05)；与此同时,动脉斑块病变的严重程度也逐渐加重,第10周动物以早期病变为主,如脂纹,而第16周动物则晚期病变如纤维斑块和钙化斑块为主。第三,对外周血单核细胞uPAR阳性率测定结果显示：实验组动物的阳性率明显高于对照组,而在3个实验组内部,随着高脂喂养周数增加,外周血单核细胞uPAR阳性率也逐渐升高,3组间存在显著差异(p<0.01)。斑块内部uPAR表达量随着病变严重程度的加重而升高。第四,对斑块内部uPAR阳性的单核巨噬细胞和泡沫细胞数量进行测定的结果显示：钙化斑块>纤维斑块>早期病变如脂纹>正常动脉管壁(p<0.05),而在纤维斑块或钙化斑块内部：脂质核心或坏死核心>纤维帽(p<0.05)。
结论：利用纯合apoE-/-C57BL雄性小鼠饲以高脂饮食能够成功建立动脉粥样硬化动物模型。随着斑块的发生及发展,小鼠外周血单核细胞uPAR表达阳性率逐渐升高。斑块内部uPAR表达量随着病变严重程度的加重而升高。所有这些结果均证实uPAR与动脉粥样硬化发生发展之间密切相关,为进一步深入研究uPAR在粥样硬化形成中的作用和机制打下了基础。
Background Fibrinolytic system exerts pleiotropic functions over the course of many physiologic and pathological processes, including cell migration, tissue remodeling and inflammation response. The urokinase-type-plasminogen-activator receptor (uPAR) is a key molecular of this system and can bind both extracellular moleculars and cell membrane moleculars, such as urokinase type plasminogen activator (uPA), vitronectin (VN), and integrins and so on. As a glycosylphosphatidylinositol-linked receptor, uPAR not only plays a key role in cell suface-associated proteolysis, but also involved in several processes not related to plasminogen activation including cellular adhesion, proliferation and chemotaxis, all of which are fundamental processes in atherogenesis. More and more studies had implicated that uPAR plays an important role in the development of atherogenesis, but the exact mechanism still remains to be elucidated.
Objectives Using the animal model of atherogenesis, we determined the levels of uPAR of monocytes or macrophages both in peripheral vessels and in atherosclerotic plaques with different degrees of atherosclerotic lesions. The purpose is to evaluate the relationship between atherogenesis and the expression of uPAR.
Methods39Male apolipoprotein E-knockout mice were randomised into6groups from the age of8weeks, including3control groups (Group1,11and III,6mice in each group) and3experimental groups (Group IV, V and VI,7mice in each group). The animals of experimental groups were fed a high-fat, cholesterol-enriched diet, while the control groups were fed a normal diet. Animals were euthanized at3-week intervals between10and16weeks of feeding, with1experimental group and1control group were euthanized each time. During dissection, the body weight of each animal were recorded, the peripheral blood and cardiovascular pathological samples were collected. The proportion of peripheral monocytes expressing uPAR was surveyed by flow cytometer. For cardiovascular pathological samples, HE staining was used to search and count the number of atherosclerotic plaques with different degrees of atherosclerotic lesions. Immunohistochemistry and immunofluorescence were employed to detect the expression of uPAR protein as well as its association with macrophages and SMC in different type of plaque.
Results First, this study built the animal model of atherogenesis successfully. The animals of experimental groups were all found different type of atherosclerotic plaques, while none of the animals in control groups was found any atherosclerotic plaques. Second, as the weeks went on, body weight of the animals in experimental groups increased rapidly. There was significant difference between these groups (p<0.05). At the same time, the degrees of atherosclerotic lesions were progressing weekly. More early lesions could be seen in animals with10weeks of high-fat diet, while more severe lesions could be found in animals with16weeks of high-fat diet. Third, Surface expression of uPAR on peripheral monocytes was significantly higher in animals with high-fat diet, compared with that in animals with normal diet (p<0.03). Even more, among the animals with high-fat diet, the expression of uPAR on peripheral monocytes increased as the fed weeks went on. There was significant difference between there experimental groups (p<0.01). Fourth, the level of uPAR in different type of plaques were detected and the results are showed as follows:calcified plaques(CP)> fibrous plaques(FP)> early lesions(EL)> normal areas(NA)(p<0.05); the core of CP or FP> the cap of CP or FP.
Conclusions Our study confirmed that male apolipoprotein E-knockout mice fed with a high-fat, cholesterol-enriched diet can build the animal model of atherogenesis successfully. With the development of atherosclerotic plaques, the expression of uPAR on mouse peripheral monocytes increased gradually. With the degree of atherosclerotic plaques developing, the level of uPAR in atherosclerotic plaques increased gradually. All these data confirm that the overexpression of uPAR both in peripheral monocytes and in advanced atherosclerotic lesions contributes to atherosclerotic plaques' development. This study provided new knowledge of monocyte/macrophage's atherogenic role by uPAR, and further investigation was required to elucidate its mechanism and the possibility of clinical application.
引文
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29. Chavakis T., Kanse SM., May AE., et al. Heamostatic factors occupy new territory: the role of the urokinase receptor system and kininogen in inflammation. Biochemical Society Transactions.2002; 30(2):168-173.
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32. Petersen LC. Kinetics of pro-urokinase/plasminogen activation:stimulation by a template formed by the urokinase receptor bound to poly-D-lysine. Eur JBiochem.1997; 245:316-323.
33. Ellis V., Behrendt N., Dan(?) K.. Plasminogen activation by receptor-bound urokinase. A kinetic study with both cell-associated and isolated receptor. J Biol Chem.1991; 266:12752-12758.
34. Ellis V., Dan(?) K.. Potentiation of plasminogen activation by an anti-urokinase monoclonal antibody due to ternary complex formation. A mechanistic model for receptor-mediated plasminogen activation. JBiol Chem.1993; 268:4806-4813.
35. Ellis V., Ploug M., Plesner T., et al. Gene expression and function of the cellular receptor for uPA (uPAR). In:Glas-Greenwalt P, ed. Fibrinolysis in Disease. Molecular and Hemovascular Aspects of Fibrinolysis. Boca Raton, Florida:CRC Press. 1995:30-42.
36. Pollanen J., Saksela O., Salonen EM., et al. Distinct localizations of urokinase-type plasminogen activator and its type 1 inhibitor under cultured human fibroblasts and sarcoma cells. J Cell Biol.1987; 104:1085-1096.
37. Pollanen J., Hedman K., Nielsen LS., et al. Ultrastructural localization of plasma membrane-associated urokinase-type plasminogen activator at focal contacts. J Cell Biol. 1988; 106:87-95.
38. Estreicher A., Muhlhauser J., Carpentier JL., et al. The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol.1990; 111:783-792.
39. Ossowski L.. Plasminogen activator dependent pathways in the dissemination of human tumor cells in the chick embryo. Cell.1988; 52:321-328.
40. Ossowski L.. In vivo invasion of modified chorioallantoic membrane by tumor cells: the role of cell surface-bound urokinase. J Cell Biol.1988; 107:2437-2445.
41. Ossowski L., Clunie G., Masucci MT., et al. In vivo paracrine interaction between urokinase and its receptor:effect on tumor cell invasion. J Cell Biol.1991; 115:1107-1112.
42. Gudewicz PW., Gilboa N.. Human urokinase-type plasminogen activator stimulates chemotaxis of human neutrophils. Biochem Biophys Res Commun.1987;147:1176-1181.
43. Gyetko MR., Todd RF., Wilkinson CC., et al. The urokinase receptor is required for human monocyte chemotaxis in vitro. J Clin Invest.1994; 93:1380-1387.
44. Gyetko MR., Sitrin RG., Fuller JA., et al. Function of the urokinase receptor (CD87) in neutrophil chemotaxis. J Leuk Biol.1995; 58:533-538.
45. Waltz DA., Chapman HA.. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. J Biol Chem.1994; 269:14746-14750.
46. Wei Y., Waltz DA., Rao N., et al. Identification of the urokinase receptor as all adhesion receptor for vitronectin. JBiol Chem.1994; 269:32380-32388.
47. Kanse SM., Kost C., Wilhelm OG., et al. The urokinase receptor is a major vitronectin-binding protein on endothelial cells. Exp Cell Res.1996; 224:344-353.
48. Xue W., Kindzelskii AL., Todd RE, et al. Physical association of complement receptor type 3 and urokinase-type plasminogen activator receptor in neutrophil membranes. J Immunol.1994; 152:4630-4640.
49. Wei Y., Lukashev M., Simon DI., et al. Regulation of integrin function by the urokinase receptor. Science.1996; 273:1551-1555.
50. Brooks PC., Clark RAF., Cheresh DA.. Requirement of vascular integrin avb3 for angiogenesis. Science.1994; 264:569-571.
51. Brooks PC., Montgomery AM., Rosenfeld M., et al. Integrin avb3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell.1994; 79:1157-1164.
52. Bohuslav J.. Urokinase plasminogen activator receptor, β2-integrins, and src-kinases within a single receptor complex of human monocytes. J Exp Med.1995; 181: 1381-1390.
53. Chaurasia P.. A region in urokinase plasminogen receptor domain Ⅲ controlling a functional association with alpha5betal integrin and tumor growth. J Biol Chem.2006; 281:14852-14863.
54. Preissner KT.. Molecular crosstalk between adhesion receptors and proteolytic cascades in vascular remodeling. Thromb Haemostas.1997; 78:88-95.
55. May AE.. Urokinase receptor (CD87) regulates leukocyte recruitment via β2-integrins in vivo. JExp Med.1998; 88:1029-1037.
56. Xue W., Mizukami I., Todd RE, et al. Urokinase-type plasminogen activator receptors associate with b1-and b3-integrins of fibrosarcoma cells-dependenceon extracellular matrix components.Canc Res.1997; 57:1682-1689.
57. Blasi F., Carmeliet P.. uPAR:a versatile signalling orchestrator. Nat Rev Mol Cell Biol.2002; 3:932-943.
58. Tarui T., Mazar AP., Cines DB., et al. Urokinase-type plasminogen activator receptor (CD87) is a ligand for integrins and mediates cell-cell interaction. J Biol Chem.2001; 276:3983-3990.
59. Waltz DA., Chapman HA.. Reversible cellular adhesion to vitronectin linked to urokinase receptor occupancy. J. Biol. Chem.1994,269:14746-14750.
60. Simon DL.. Mac-1 (CD11b/CD 18) and the urokinase receptor (CD87) from a functional unit on monocytic cells. Blood.1996,88:3185-3194.
61. Ferias-Eisner, R. Thye urokinase plasminogen activator receptor (uPAR) is preferentially indeced by nerve growth factors in PC 12 pheomocromocytoma cells and is required for NGF-driven differentiation. J. Neurosci.2000,20:230-239.
62. Rabbani SA.. Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J. Biol. Chem.1992,267:14151-14156.
63. Yu W., Kim J., Ossowski L.. Reduction in surface urokinase receptor forces malignant cells into a protracted state of dormancy. J. Cell Biol.1997,137:767-777.
64. Aguirre-Ghiso JA., Kovalski K., Ossowski L.. Tumor dormancy indeced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J. cell Biol.1999,147:89-104.
65. Aguirre-Ghiso JA., Liu D., Mignatti A., et al. Urokinase receptor and fibronectin regulate the ERK (MAPK) to p38 (MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol. Biol. Cell.2001,12:863-879.
66. Sukhova GK., Shi GP., Simon DL. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998,102:576-583.
67. Galis ZS., Sukhova GK., Lark MW., et al. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest.1994;94:2493-2503.
68. Herman MP., Sukhova GK., Libby P., et al. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma:a novel collagenolytic pathway suggested by transcriptional profiling. Circulation.,2001; 104:1899-1904.
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