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系統識別號 U0026-0308201200162400
論文名稱(中文) 探討凝血酶調節素在血管病變中的角色
論文名稱(英文) The Role of Thrombomodulin in Angiopathy
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) Department of Biochemistry and Molecular Biology
學年度 100
學期 2
出版年 101
研究生(中文) 簡如君
研究生(英文) Ju-Chun Chien
學號 s16994027
學位類別 碩士
語文別 英文
論文頁數 64頁
口試委員 指導教授-吳華林
口試委員-施桂月
口試委員-張文粲
口試委員-林淑華
中文關鍵字 血管病變  凝血酶調節素  高血糖  視網膜病變  高氧誘導視網膜病變動物模式 
英文關鍵字 angiopathy  thrombomodulin  hyperglycemia  retinopathy  oxygen-induced retinopathy 
學科別分類
中文摘要 視網膜病變屬於一種微血管病變,是造成我國中老年人口失明的主要原因。在過去臨床數據顯示,糖尿病視網膜病變者的血液中,相對於未病變者,有大量的游離式凝血酶調節素(soluble thrombomodulin, soluble TM) 及HMGB-1 (high mobility group box-1)蛋白質表現,而這兩者都和視網膜病變的嚴重程度呈正相關。TM是一種表現於血管內皮細胞的穿膜醣蛋白,目前已知其類凝集素功能區(lectin-like domain, TMD1)除了具有抗血管新生特性外,還會阻擾HMGB-1所誘導的發炎反應。因此本篇研究主要探討高濃度葡萄糖環境下,血管內皮細胞中TM和HMGB-1的表現,以及重組TMD1蛋白(rTMD1)是否具有治療視網膜病變的潛力。結果顯示,在不影響細胞存活率的高糖條件下,內皮細胞中的TM與其轉錄因子Kruppel-like factor 2 (KLF2)兩者的mRNA受到抑制,且TM蛋白質表現量也下降。同時,高濃度葡萄糖也會刺激內皮細胞核中的HMGB-1分泌至細胞外。此外,rhHMGB-1除了會提升內皮細胞增生,也會促使其IB-降解並且抑制TM 的mRNA和蛋白質表現。另外,利用氧氣誘導幼鼠視網膜病變後,給予rTMD1能夠顯著抑制病理性的血管新生以及促使正常血管的生成。綜合以上結果,HMGB-1可能是高濃度葡萄糖抑制內皮細胞中TM表現的機制之一,除此之外,rTMD1具有成為抑制視網膜病變惡化的藥物潛能。
英文摘要 Retinopathy, including retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR), is a microangiopathy in retina. PDR remains the leading cause of preventable blindness in working-aged people. The elevated high-mobility group box 1 (HMGB1) and soluble thrombomodulin (TM) in plasma of diabetic patients have been revealed. In addition, TM interferes with HMGB1 signaling leading to inflammation via its lectin-like domain. However, the regulation of TM and HMGB1 by high glucose condition is unclear. Therefore, the expression of TM and HMGB-1 in high glucose condition was investigated in this study. Furthermore, therapeutic strategy to suppress neo-angiogenesis in retina by using anti-inflammatory and anti-angiogenic recombinant lectin-like domain of TM (rTMD1) was evaluated. The results showed that the expression of TM and its transcription factor, Kruppel-like factor 2 (KLF2), were decreased in endothelial cells upon culture in high glucose condition. HMGB-1 was released to supernatant from endothelial cells while cell viability was not affected by high glucose condition. In addition, rhHMGB1 promoted the degradation of IB- and inhibited the expression of TM. By using mouse model of oxygen induced retinopathy, the pathological neo-vascularization was suppressed and physiological vessel re-growth was promoted in retina of mice with rTMD1 treatment. Taken together, HMGB-1 may be a mediator of down-regulation of TM in endothelial cells in hyperglycemia. In addition, rTMD1 could be a potential therapeutic agent for PDR.
論文目次 Abstract in Chinese........................................1
Abstract...................................................2
Acknowledgement............................................3
Contents...................................................5
Table of Contents..........................................6
Figure Contents............................................8
Appendix Contents..........................................8
Chapter 1 Introduction.....................................9
1-1 Angiopathy.............................................9
1-1.1 Diabetic Angiopathy................................9
1-1.2 Diabetic Retinopathy...............................9
1-1.3 Retinopathy of Prematurity........................10
1-2 Thrombomoudulin...................................11
1-2.1 Structure and Functions of TM.....................11
1-2.2 Regulation of TM..................................11
1-2.3 Soluble TM and Angiopathy.........................12
1-3 High Mobility Group Box-1.........................13
1-3.1 Properties of HMGB-1..............................13
1-3.2 HMGB-1 and Angiopathy.............................14
1-3.3 HMGB-1 and TM.....................................14
1-4 Objectives of Study...............................15
1-4.1 The Expression of TM and HMGB1 in Endothelial Cells in High Glucose Condition....................15
1-4.2 Application of rTMD1 to Retinopathy..............15

Chapter 2 Materials and Methods..........................16
2-1 Gel Electrophoresis and Western Blot..............16
2-2 Gel Staining......................................19
2-3 Cell Model and Culture Condition..................19
2-4 Cell Viability Assay..............................21
2-5 RNA Extraction, RT-PCR and Quantitative Real Time PCR...........21
2-6 Immunocytochemistry...............................27
2-7 Oxygen Induced Retinopathy in Mouse Mode..........29
2-8 Statistic Analysis................................32
Chapter 3 Results.........................................33

Chapter 4 Discussion......................................36

Chapter 5 Prospects.......................................40

References................................................52
Abbreviations.............................................64

Figure Contents
Fig. 1 Cell viability is not affected by high glucose
concentration.....................................41

Fig. 2 The expression of TM in HUVECs is dose-dependently
suppressed by high glucose concentration..........42

Fig. 3 TM and KLF2 in HUVECs are transcriptionally down-
regulated by high glucose concentration...........43

Fig. 4 TM in endothelial cells is down-regulated
transcriptionally by high glucose concentration...44

Fig. 5 HMGB-1 is released to medium from HUVECs in
high glucose concentration........................45

Fig. 6 Cell growth is elevated by rhHMGB-1...............46

Fig. 7 rhHMGB-1 promotes the degradation of IB- and
suppresses the expression of TM...................47

Fig. 8 TM is suppressed dose-dependently in
transcriptional level in HUVECs by rhHMGB-1.......48

Fig. 9 Pathological neo-vascularization is suppressed in
retinas of mice with rTMD1 treatment..............49

Fig. 10 Physiological vessel re-growth is promoted in
retinas of mice with rTMD1 treatment..............50

Fig. 11 Schematic representation of the interaction of TM
and HMGB-1 in hyperglycemia.......................51

Appendix Contents
I. Schematic domains of TM with corresponding functions...59
II.DNA and amino acid sequences of human TM...............60


參考文獻 1 Antonetti, D. A., Klein, R. & Gardner, T. W. Endothelial dysfunction and pathogenesis of diabetic angiopathy. The New England journal of medicine 366, 1227- 1239, doi:10.1056/NEJMra1005073 (2012).
2 Creager, M. A., Luscher, T. F., Cosentino, F. & Beckman, J. A. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 108, 1527-1532, doi:10.1161/01.cir.0000091257.27563.32 (2003).
3 Luscher, T. F., Creager, M. A., Beckman, J. A. & Cosentino, F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part II. Circulation 108, 1655-1661, doi:10.1161/01.cir.0000089189.70578.e2 (2003).
4 Tooke, J. E. Possible pathophysiological mechanisms for diabetic angiopathy in type 2 diabetes. Journal of diabetes and its complications 14, 197-200 (2000).
5 Ho, F. M. et al. High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-kappaB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway. Cellular signalling 18, 391-399, doi:10.1016/j.cellsig.2005.05.009 (2006).
6 Watada, H., Azuma, K. & Kawamori, R. Glucose fluctuation on the progression of diabetic macroangiopathy--new findings from monocyte adhesion to endothelial cells. Diabetes research and clinical practice 77 Suppl 1, S58-61, doi:10.1016/j.diabres.2007.01.034 (2007).
7 Pickup, J. C. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes care 27, 813-823 (2004).
8 Stehouwer, C. D. et al. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 51, 1157-1165 (2002).
9 Porta, M., La Selva, M., Molinatti, P. & Molinatti, G. M. Endothelial cell function in diabetic microangiopathy. Diabetologia 30, 601-609 (1987).
10 Zatz, R. & Brenner, B. M. Pathogenesis of diabetic microangiopathy. The hemodynamic view. The American journal of medicine 80, 443-453 (1986).
11 Joussen, A. M. et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16, 438-440, doi:10.1096/fj.01-0707fje (2002).
12 Kowluru, R. A. & Odenbach, S. Role of interleukin-1beta in the pathogenesis of diabetic retinopathy. The British journal of ophthalmology 88, 1343-1347, doi:10.1136/bjo.2003.038133 (2004).
13 Sapieha, P. et al. Proliferative retinopathies: angiogenesis that blinds. The international journal of biochemistry & cell biology 42, 5-12, doi:10.1016/j.biocel.2009.10.006 (2010).
14 Klein, R., Klein, B. E., Moss, S. E., Davis, M. D. & DeMets, D. L. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA : the journal of the American Medical Association 260, 2864-2871 (1988).
15 Nicholson, B. P. & Schachat, A. P. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 248, 915-930, doi:10.1007/s00417-010-1315-z (2010).
16 Sane, D. C., Anton, L. & Brosnihan, K. B. Angiogenic growth factors and hypertension. Angiogenesis 7, 193-201, doi:10.1007/s10456-004-2699-3 (2004).
17 Drolet, D. W. et al. Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharmaceutical research 17, 1503-1510 (2000).
18 Roth, A. M. Retinal vascular development in premature infants. American journal of ophthalmology 84, 636-640 (1977).
19 Chen, J. & Smith, L. E. Retinopathy of prematurity. Angiogenesis 10, 133-140, doi:10.1007/s10456-007-9066-0 (2007).
20 Dorrell, M. I., Aguilar, E. & Friedlander, M. Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Investigative ophthalmology & visual science 43, 3500-3510 (2002).
21 Soff, G. A., Jackman, R. W. & Rosenberg, R. D. Expression of thrombomodulin by smooth muscle cells in culture: different effects of tumor necrosis factor and cyclic adenosine monophosphate on thrombomodulin expression by endothelial cells and smooth muscle cells in culture. Blood 77, 515-518 (1991).
22 Raife, T. J. et al. Thrombomodulin expression by human keratinocytes. Induction of cofactor activity during epidermal differentiation. The Journal of clinical investigation 93, 1846-1851, doi:10.1172/jci117171 (1994).
23 McCachren, S. S., Diggs, J., Weinberg, J. B. & Dittman, W. A. Thrombomodulin expression by human blood monocytes and by human synovial tissue lining macrophages. Blood 78, 3128-3132 (1991).
24 Maillard, C. et al. Thrombomodulin is synthesized by osteoblasts, stimulated by 1,25-(OH)2D3 and activates protein C at their cell membrane. Endocrinology 133, 668-674 (1993).
25 Geudens, N. et al. The lectin-like domain of thrombomodulin protects against ischaemia-reperfusion lung injury. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology 32, 862-870, doi:10.1183/09031936.00157107 (2008).
26 Conway, E. M. et al. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. The Journal of experimental medicine 196, 565-577 (2002).
27 Shi, C. S. et al. Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response. Blood 112, 3661-3670, doi:10.1182/blood-2008-03-142760 (2008).
28 Van de Wouwer, M. et al. The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis. Journal of thrombosis and haemostasis : JTH 4, 1813-1824, doi:10.1111/j.1538-7836.2006.02033.x (2006).
29 Abeyama, K. et al. The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. The Journal of clinical investigation 115, 1267-1274, doi:10.1172/jci22782 (2005).
30 Kuo, C. H. et al. The recombinant lectin-like domain of thrombomodulin inhibits angiogenesis through interaction with Lewis Y antigen. Blood 119, 1302-1313, doi:10.1182/blood-2011-08-376038 (2012).
31 Huang, H. C. et al. Thrombomodulin-mediated cell adhesion: involvement of its lectin-like domain. The Journal of biological chemistry 278, 46750-46759, doi:10.1074/jbc.M305216200 (2003).
32 Owen, W. G. & Esmon, C. T. Functional properties of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. The Journal of biological chemistry 256, 5532-5535 (1981).
33 Shi, C. S. et al. Evidence of human thrombomodulin domain as a novel angiogenic factor. Circulation 111, 1627-1636, doi:10.1161/01.cir.0000160364.05405.b5 (2005).
34 Lohi, O., Urban, S. & Freeman, M. Diverse substrate recognition mechanisms for rhomboids; thrombomodulin is cleaved by Mammalian rhomboids. Current biology : CB 14, 236-241, doi:10.1016/j.cub.2004.01.025 (2004).
35 Sohn, R. H. et al. Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B. Blood 105, 3910-3917, doi:10.1182/blood-2004-03-0928 (2005).
36 Grey, S. T., Csizmadia, V. & Hancock, W. W. Differential effect of tumor necrosis factor-alpha on thrombomodulin gene expression by human monocytoid (THP-1) cell versus endothelial cells. International journal of hematology 67, 53-62 (1998).
37 SenBanerjee, S. et al. KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation. The Journal of experimental medicine 199, 1305-1315, doi:10.1084/jem.20031132 (2004).
38 Fang, Y., Davies, P. F. C. I. N. A. T. V. B. A. & Pmid. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arteriosclerosis, thrombosis, and vascular biology 32, 979-987, doi:10.1161/atvbaha.111.244053 (2012).
39 Lin, Z. et al. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circulation research 96, e48-57, doi:10.1161/01.RES.0000159707.05637.a1 (2005).
40 Bhattacharya, R. et al. Inhibition of vascular permeability factor/vascular endothelial growth factor-mediated angiogenesis by the Kruppel-like factor KLF2. The Journal of biological chemistry 280, 28848-28851, doi:10.1074/jbc.C500200200 (2005).
41 Lee, H. Y., Youn, S. W., Oh, B. H. & Kim, H. S. Kruppel-like factor 2 suppression by high glucose as a possible mechanism of diabetic vasculopathy. Korean circulation journal 42, 239-245, doi:10.4070/kcj.2012.42.4.239 (2012).
42 Wu, Y. et al. ERK5 Contributes to VEGF Alteration in Diabetic Retinopathy. Journal of ophthalmology 2010, 465824, doi:10.1155/2010/465824 (2010).
43 Allen, K. L., Hamik, A., Jain, M. K. & McCrae, K. R. Endothelial cell activation by antiphospholipid antibodies is modulated by Kruppel-like transcription factors. Blood 117, 6383-6391, doi:10.1182/blood-2010-10-313072 (2011).
44 Wang, L. et al. Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation. American journal of respiratory cell and molecular biology 36, 497-503, doi:10.1165/rcmb.2005-0425OC (2007).
45 Uehara, S., Gotoh, K. & Handa, H. Separation and characterization of the molecular species of thrombomodulin in the plasma of diabetic patients. Thrombosis research 104, 325-332 (2001).
46 Nakano, M. et al. Elevation of soluble thrombomodulin antigen levels in the serum and urine of streptozotocin-induced diabetes model rats. Thrombosis research 99, 83-91 (2000).
47 Lin, S. M. et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Critical care medicine 36, 683-689, doi:10.1097/ccm.0b013e31816537d8 (2008).
48 Matondo Maya, D. W., Mewono, L., Nkoma, A. M., Issifou, S. & Mavoungou, E. Markers of vascular endothelial cell damage and P. falciparum malaria: association between levels of both sE-selectin and thrombomodulin, and cytokines, hemoglobin and clinical presentation. European cytokine network 19, 123-130, doi:10.1684/ecn.2008.0129 (2008).
49 Tanaka, A., Ishii, H., Hiraishi, S., Kazama, M. & Maezawa, H. Increased thrombomodulin values in plasma of diabetic men with microangiopathy. Clinical chemistry 37, 269-272 (1991).
50 Salomaa, V. et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study. Lancet 353, 1729-1734 (1999).
51 Wu, K. K. Soluble thrombomodulin and coronary heart disease. Current opinion in lipidology 14, 373-375, doi:10.1097/01.mol.0000083766.66245.44 (2003).
52 Wu, K. K. et al. Interaction between soluble thrombomodulin and intercellular adhesion molecule-1 in predicting risk of coronary heart disease. Circulation 107, 1729-1732, doi:10.1161/01.cir.0000064894.97094.4f (2003).
53 Moll, S. et al. Phase I study of a novel recombinant human soluble thrombomodulin, ART-123. Journal of thrombosis and haemostasis : JTH 2, 1745-1751, doi:10.1111/j.1538-7836.2004.00927.x (2004).
54 Nakashima, M., Kanamaru, M., Umemura, K. & Tsuruta, K. Pharmacokinetics and safety of a novel recombinant soluble human thrombomodulin, ART-123, in healthy male volunteers. Journal of clinical pharmacology 38, 40-44 (1998).
55 Saito, H. et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. Journal of thrombosis and haemostasis : JTH 5, 31-41, doi:10.1111/j.1538-7836.2006.02267.x (2007).
56 Bell, C. W., Jiang, W., Reich, C. F., 3rd & Pisetsky, D. S. The extracellular release of HMGB1 during apoptotic cell death. American journal of physiology. Cell physiology 291, C1318-1325, doi:10.1152/ajpcell.00616.2005 (2006).
57 Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191-195, doi:10.1038/nature00858 (2002).
58 Gardella, S. et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO reports 3, 995-1001, doi:10.1093/embo-reports/kvf198 (2002).
59 Schmidt, A. M., Yan, S. D., Yan, S. F. & Stern, D. M. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. The Journal of clinical investigation 108, 949-955, doi:10.1172/jci14002 (2001).
60 Fiuza, C. et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101, 2652-2660, doi:10.1182/blood-2002-05-1300 (2003).
61 Biscetti, F. et al. High-mobility group box-1 protein promotes angiogenesis after peripheral ischemia in diabetic mice through a VEGF-dependent mechanism. Diabetes 59, 1496-1505, doi:10.2337/db09-1507 (2010).
62 Lin, Q. et al. High-mobility group box-1 mediates toll-like receptor 4-dependent angiogenesis. Arteriosclerosis, thrombosis, and vascular biology 31, 1024-1032, doi:10.1161/atvbaha.111.224048 (2011).
63 Huang, W. et al. HMGB1 Increases Permeability of the Endothelial Cell Monolayer via RAGE and Src Family Tyrosine Kinase Pathways. Inflammation, doi:10.1007/s10753-011-9325-5 (2011).
64 Taniguchi, N. et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis and rheumatism 48, 971-981, doi:10.1002/art.10859 (2003).
65 Ma, C. Y. et al. Elevated plasma level of HMGB1 is associated with disease activity and combined alterations with IFN-alpha and TNF-alpha in systemic lupus erythematosus. Rheumatology international 32, 395-402, doi:10.1007/s00296-010-1636-6 (2012).
66 Yao, D. & Brownlee, M. Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59, 249-255, doi:10.2337/db09-0801 (2010).
67 Devaraj, S., Dasu, M. R., Park, S. H. & Jialal, I. Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes. Diabetologia 52, 1665-1668, doi:10.1007/s00125-009-1394-8 (2009).
68 Win, M. T. et al. Regulation of RAGE for attenuating progression of diabetic vascular complications. Experimental diabetes research 2012, 894605, doi:10.1155/2012/894605 (2012).
69 Yan, X. X. et al. Increased serum HMGB1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients. Atherosclerosis 205, 544-548, doi:10.1016/j.atherosclerosis.2008.12.016 (2009).
70 Soro-Paavonen, A. et al. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 57, 2461-2469, doi:10.2337/db07-1808 (2008).
71 Kim, J., Sohn, E., Kim, C. S., Jo, K. & Kim, J. S. The role of high-mobility group box-1 protein in the development of diabetic nephropathy. American journal of nephrology 33, 524-529, doi:10.1159/000327992 (2011).
72 Alleva, L. C. O. N. J. I. J. & Pmid. Comment on "Cutting edge: Extracellular high mobility group box-1 protein is a proangiogenic cytokine". Journal of immunology (Baltimore, Md. : 1950) 176, 4512; author reply 4513 (2006).
73 Qiu, Y. et al. HMGB1 promotes lymphangiogenesis of human lymphatic endothelial cells in vitro. Medical oncology (Northwood, London, England), doi:10.1007/s12032-010-9778-7 (2010).
74 El-Asrar, A. M. et al. High-mobility group box-1 and biomarkers of inflammation in the vitreous from patients with proliferative diabetic retinopathy. Molecular vision 17, 1829-1838 (2011).
75 El-Asrar, A. M., Missotten, L. & Geboes, K. Expression of high-mobility groups box-1/receptor for advanced glycation end products/osteopontin/early growth response-1 pathway in proliferative vitreoretinal epiretinal membranes. Molecular vision 17, 508-518 (2011).
76 Ito, T. et al. Proteolytic cleavage of high mobility group box 1 protein by thrombin-thrombomodulin complexes. Arteriosclerosis, thrombosis, and vascular biology 28, 1825-1830, doi:10.1161/atvbaha.107.150631 (2008).
77 Nagato, M., Okamoto, K., Abe, Y., Higure, A. & Yamaguchi, K. Recombinant human soluble thrombomodulin decreases the plasma high-mobility group box-1 protein levels, whereas improving the acute liver injury and survival rates in experimental endotoxemia. Critical care medicine 37, 2181-2186, doi:10.1097/CCM.0b013e3181a55184 (2009).
78 Connor, K. M. et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nature protocols 4, 1565-1573, doi:10.1038/nprot.2009.187 (2009).
79 Baumgartner-Parzer, S. M. et al. High-glucose--triggered apoptosis in cultured endothelial cells. Diabetes 44, 1323-1327 (1995).
80 Sheu, M. L. et al. High glucose induces human endothelial cell apoptosis through a phosphoinositide 3-kinase-regulated cyclooxygenase-2 pathway. Arteriosclerosis, thrombosis, and vascular biology 25, 539-545, doi:10.1161/01.ATV.0000155462.24263.e4 (2005).
81 Rabadi, M. M. et al. Interaction between uric acid and HMGB1 translocation and release from endothelial cells. American journal of physiology. Renal physiology 302, F730-741, doi:10.1152/ajprenal.00520.2011 (2012).
82 Giebel, S. J., Menicucci, G., McGuire, P. G. & Das, A. Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrier. Laboratory investigation; a journal of technical methods and pathology 85, 597-607, doi:10.1038/labinvest.3700251 (2005).
83 Jin, M. et al. Matrix metalloproteinases in human diabetic and nondiabetic vitreous. Retina (Philadelphia, Pa.) 21, 28-33 (2001).
84 Yildirim, N. et al. The relationship between plasma MMP-9 and TIMP-2 levels and intraocular pressure elevation in diabetic patients after intravitreal triamcinolone injection. Journal of glaucoma 17, 253-256, doi:10.1097/IJG.0b013e31815c3a07 (2008).
85 Das, A., McLamore, A., Song, W. & McGuire, P. G. Retinal neovascularization is suppressed with a matrix metalloproteinase inhibitor. Archives of ophthalmology 117, 498-503 (1999).
86 Qiu, J. et al. High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia. Stroke; a journal of cerebral circulation 41, 2077-2082, doi:10.1161/strokeaha.110.590463 (2010).
87 Conway, E. M. Thrombomodulin and its role in inflammation. Seminars in immunopathology 34, 107-125, doi:10.1007/s00281-011-0282-8 (2012).
88 Sachdev, U. et al. High mobility group box 1 promotes endothelial cell angiogenic behavior in vitro and improves muscle perfusion in vivo in response to ischemic injury. Journal of vascular surgery : official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 55, 180-191, doi:10.1016/j.jvs.2011.07.072 (2012).
89 Dvoriantchikova, G. et al. The high-mobility group box-1 nuclear factor mediates retinal injury after ischemia reperfusion. Investigative ophthalmology & visual science 52, 7187-7194, doi:10.1167/iovs.11-7793 (2011).
90 Davies, M. H., Eubanks, J. P. & Powers, M. R. Microglia and macrophages are increased in response to ischemia-induced retinopathy in the mouse retina. Molecular vision 12, 467-477 (2006).
91 Adams, R. H. & Eichmann, A. Axon guidance molecules in vascular patterning. Cold Spring Harbor perspectives in biology 2, a001875, doi:10.1101/cshperspect.a001875 (2010).
92 Stone, J. et al. Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial growth factor (VEGF) expression by neuroglia. The Journal of neuroscience : the official journal of the Society for Neuroscience 15, 4738-4747 (1995).
93 Lobov, I. B. et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proceedings of the National Academy of Sciences of the United States of America 104, 3219-3224, doi:10.1073/pnas.0611206104 (2007).
94 Stahl, A. et al. The mouse retina as an angiogenesis model. Investigative ophthalmology & visual science 51, 2813-2826, doi:10.1167/iovs.10-5176 (2010).
95 Parmar, K. M. et al. Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. The Journal of biological chemistry 280, 26714-26719, doi:10.1074/jbc.C500144200 (2005).
96 Gracia-Sancho, J., Villarreal, G., Jr., Zhang, Y. & Garcia-Cardena, G. Activation of SIRT1 by resveratrol induces KLF2 expression conferring an endothelial vasoprotective phenotype. Cardiovascular research 85, 514-519, doi:10.1093/cvr/cvp337 (2010).
97 Donnelly, L. E. et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. American journal of physiology. Lung cellular and molecular physiology 287, L774-783, doi:10.1152/ajplung.00110.2004 (2004).
98 Holmes-McNary, M. & Baldwin, A. S., Jr. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer research 60, 3477-3483 (2000).
99 Manna, S. K., Mukhopadhyay, A. & Aggarwal, B. B. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. Journal of immunology (Baltimore, Md. : 1950) 164,
100 呂翼均
The lectin-like domain of thrombomodulin inhibits murine melanoma invasion through regulating matrix metalloproteinase
國立成功大學生物化學暨分子生物學研究所 碩士論文
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