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研究生:鍾新華
研究生(外文):Hsin-Hua Chung
論文名稱:血栓調節因子之基因變異與心臟移植後血管病變發生之相關性及其對血管平滑肌前驅細胞移行之影響
論文名稱(外文):The roles of thrombomodulin in vascular smooth muscle progenitor cell migration and in cardiac allograft vasculopathy after heart transplantation
指導教授:施俊哲施俊哲引用關係林豐彥
指導教授(外文):Chun-Che ShihFeng-Yen Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:114
中文關鍵詞:心臟移植血管病變血栓調節因子血管平滑肌前驅細胞單一核苷酸多型性
外文關鍵詞:cardiac allograft vasculopathythrombomodulinvascular smooth muscle progenitor cellssingle nucleotide polymorphism
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中文摘要
心臟移植後血管病變(cardiac allograft vasculopathy; CAV)的血管中,有許多平滑肌細胞(smooth muscle cells; SMCs)堆積,科學家認為這是造成血管狹窄與阻塞的主要原因。健康動脈的SMC上,無法偵測到血栓調節因子(thrombomodulin; TM)的表現;但是在動脈粥狀硬化或血管損傷而誘發增生的血管內層中,血管平滑肌細胞(vascular smooth muscle cells; VSMCs)之TM表現量明顯增加。近來有許多研究發現,血管內皮損傷會導致內皮前驅細胞(endothelial progenitor cells; EPCs)上TM表現減少,使其移行變慢。因此科學家推測,細胞上TM的表現,可能與其增生(proliferation)、移行(migration)、回歸(homing)能力有關;然而TM在血管平滑肌前驅細胞(vascular smooth muscle progenitor cells; VSMPCs)的功能仍然不清楚。另外,有文獻指出TM的單一核苷酸多型性(Single nucleotide polymorphism; SNP)在心臟血管疾病中扮演著重要角色;但TM的SNP與CAV發生之相關性也是未知。因此本研究探討TM在VSMPCs移行之角色及其與CAV發生之相關性。
本研究首先分析心臟移植病患臨床血液檢體的TM上之SNP。由心臟移植病患TM上的兩個核苷酸變異點,分別為promoter上的G-33A與exon上的C1418T,以及病患近五年的病歷報告;比較心臟移植術後第三年與第一年,我們發現C1418T的SNP點若帶有T,其CD8/CD4 ratio偏高、Masson's trichrome staining呈現陽性以及ISHLT-WF1990 grade (International society for heart lung transplantation grade)分數偏高的比例較多。研究結果顯示,TM之C1418T此SNP點與短期到中期的心臟移植後排斥反應有顯著關聯。
另外以人類VSMPCs來研究其移行與TM的相關性。本實驗以人類周邊靜脈血分離出單核球細胞,再將其刺激使之分化成VSMPCs,並以酯多醣(lipopolysaccharide, LPS)或人類高遷移率族蛋白B1(high mobility group box 1, HMGB1)處理,發現其TM表現量減少且細胞移行增加。為了進一步印證,我們將TM的siRNA送入VSMPCs內,抑制其TM的表現,結果與以LPS或人類HMGB1處理後相同。証實,當VSMPCs的TM表現量減少,細胞移行反而增加。
未來,希望能將上述VSMPCs的細胞實驗與TM的SNP得到的結果交叉研究,進一步找出TM在VSMPCs分化與功能之角色及其誘發CAV之可能性。
Abstrate
In the vessel of cardiac allograft vasculopathy (CAV), there are many smooth muscle cells (SMCs) accumulation. Scientists predict it is the main cause of restenosis. In healthy vascular smooth muscle cell (VSMC), thrombomodulin (TM) expression is not detected but it is increased in atherosclerosis and injured blood vessel. Many studies demonstrated that the expression of TM in endothelial progenitor cell (EPC) is decreased by injured endothelial, and resulted in weakly migration. Scientists predict that the TM of cell is associated with proliferation, migration and homing. But the role of TM in vascular smooth muscle progenitor cell (VSMPC) remains unclear. In addition, previous studies also demonstrated that the TM single nucleotide polymorphisms (SNPs) play an important role in cardiovascular disease. But the association of TM SNPs with inducing the CAV also remains unclear. Therefore, our study investigated the roles of TM in VSMPC migration and in CAV.
We selected the two SNPs of TM. One is G-33A on promoter, another is C1418T on exon, and examined these two SNPs by amplification refractory mutation system (ARMS) and restriction fragment length polymorphism (RFLP) to analysis the patient of heart transplanted. Then we explored the possibility of CAV by medical records of patients near five years and SNPs result. Compared with two group which is first and third year of cardiac transplantation. The results showed the patient whose TM gene sequence have T allele on C1418T SNP has higher CD8/CD4 ratio, positive Masson's trichrome staining and higher ISHLT-WF1990 grade scores. Our results support a significant association of the TM C1418T SNP with allograft rejection after heart transplantation in the short- to medium-term. Besides, we isolated the mononuclear cell from human peripheral blood and differentiated it into SMPC. After treating with lipopolysaccharide (LPS) or human high mobility group box 1 (HMGB1), TM expression was decreased and migration was increased in SMPC. To prove this finding, we transfected TM siRNA into the SMPC to knock-down TM expression, then SMPC migration became weakly by wound-healing assay. This result is the same with LPS or human HMGB1 treatment. The examination confirmed, the SMPC migration is became weakly when TM expression is decreased.
Further, we hope to study crossover with our result of VSMPCs and TM SNPs. Finally, to find the association of TM on VSMPCs with inducing the probability of CAV after heart transplantation.
目錄
中文摘要------------------------------------------------- 1
英文摘要------------------------------------------------- 2
縮寫表-------------------------------------------------- 3
壹、前言------------------------------------------------- 6
一、心臟移植---------------------------------------------- 7
二、移植排斥---------------------------------------------- 8
2-1 T細胞的調控
2-2 抗體排斥反應
2-3 慢性排斥反應
2-4排斥反應的內源性危險信號:HMGB1
三、心臟移植後血管病變(cardiac allograft vasculopathy)---- 12
四、血栓調節因子與心臟血管疾病----------------------------- 13
4-1 血栓調節因子
4-2 血栓調節因子之結構與功能
4-3 血栓調節因子與心血管疾病及血管細胞之相關性
4-4 血栓調節因子的基因多型性與心臟血管疾病
五、疾病與基因多型性-------------------------------------- 16
六、血管平滑肌前驅細胞------------------------------------ 18
6-1 血管平滑肌細胞
6-2 血管平滑肌前驅細胞
6-3 血管平滑肌前驅細胞與血管病變
七、研究目的--------------------------------------------- 20
貳、材料與方法------------------------------------------- 21
一、心臟移植病患臨床血液檢體及Genomic DNA的純化------------- 22
二、核酸限制酶截切片段長度多型性(RFLP)-------------------- 22
2-1 PCR Conditions for RFLP Genotyping
2-2 RFLP
三、擴增受阻突變系統聚合酶連鎖反應(ARMS)------------------ 24
3-1 PCR Conditions for ARMS Genotyping
3-2 ARMS
四、病歷查詢與資料分析彙整--------------------------------- 26
4-1量化組織切片病理分析和ISHLT-WF1990 grades
4-2 統計
五、細胞培養--------------------------------------------- 27
5-1 血管平滑肌前驅細胞
5-2 血管內皮前驅細胞
5-3 人類主動脈平滑肌細胞
六、血管平滑肌前驅細胞的鑑定------------------------------- 28
6-1 細胞免疫染色法
6-2 流式細胞儀法
七、血管平滑肌前驅細胞上血栓調節因子的表現------------------- 29
7-1 流式細胞儀法
八、血管平滑肌前驅細胞及人類主動脈平滑肌細胞以LPS處理後,其血栓調節因子表現量----------------------------------------------- 29
8-1 流式細胞儀法
8-2 西方墨點轉漬分析法
九、血管平滑肌前驅細胞以HMGB1處理後,其血栓調節因子表現量----- 30
9-1 流式細胞儀法
十、血栓調節因子基因表現載體(vector)的建構------------------ 31
十一、以Neon轉染系統將基因表現載體送入細胞內----------------- 31
十二、細胞移行實驗---------------------------------------- 31
12-1 LPS處理血管平滑肌前驅細胞及人類主動脈平滑肌細胞並觀察其移行能力
12-2 HMGB1處理血管平滑肌前驅細胞及人類主動脈平滑肌細胞並觀察其移行能力
12-2 經血栓調節因子siRNA轉染後的血管平滑肌前驅細胞之移行能力
叁、實驗結果--------------------------------------------- 33
第一部分 血酸調節因子基因多型性與心臟移植後血管病變之相關性---- 34
一、血酸調節因子表現子上單一核苷酸多型性點C1418T對心臟移植後血管病變之關連性
1-1接受心臟移植手術前的病患資料
1-2心臟移植患者手術後的生化數值
1-3在CT/ TT基因型的患者有慢性排斥的反應
第二部份 血管平滑肌前驅細胞的鑑定--------------------------- 36
一、血管前驅細胞的分化
二、血管平滑肌前驅細胞的鑑定
2-1 細胞免疫染色
2-2 流式細胞儀分析
第三部份 血栓調節因子對血管平滑肌前驅細胞移行的影響----------- 38
一、血管平滑肌前驅細胞受LPS刺激後移行的影響
1-1 細胞傷口癒合檢測
1-2 細胞免疫染色
二、血管平滑肌前驅細胞受LPS刺激後血栓調節因子影響
2-1 流式細胞儀分析
2-2 西方墨點轉漬法
三、血管平滑肌前驅細胞受HMGB1刺激後血栓調節因子影響
3-1 流式細胞儀分析
四、血管平滑肌前驅細胞受HMGB1刺激後移行的影響
4-1 細胞傷口癒合檢測
五、血栓調節因子對於血管平滑肌前驅細胞移行的影響
5-1 細胞傷口癒合檢測
肆、討論------------------------------------------------- 43
第一部份 血酸調節因子基因多型性與心臟移植後血管病變之相關性---- 44
第二部份 血管平滑肌前驅細胞的鑑定--------------------------- 46
第三部份 血栓調節因子對血管平滑肌前驅細胞移行的影響----------- 48
伍、結論------------------------------------------------- 51
陸、未來發展--------------------------------------------- 53
柒、參考文獻--------------------------------------------- 56
捌、圖表------------------------------------------------- 74
玖、補充資料-------------------------------------------- 108
補充資料表1--------------------------------------------- 109
補充資料表2--------------------------------------------- 110
補充資料表3--------------------------------------------- 112
補充資料表4--------------------------------------------- 114

參考文獻
1. O'Connell JB, Bourge RC, Costanzo-Nordin MR, Driscoll DJ, Morgan JP, Rose EA, Uretsky BF. Cardiac transplantation: recipient selection, donor procurement, and medical follow-up. A statement for health professionals from the Committee on Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation. 1992;86:1061-1079.

2. Andreas S, Mihail H, Sieglinde K, Robert F, Barbara LH, Nicole H, Zhou Z, Shamima A, Uwe S, Florian KT, Marcus L, Andreas KN, Ingo K, Bruno R, Volker K, Christian W, Sohn HY. CD34+CD140b+ cells and circulating CXCL12 correlate with the angiographically assessed severity of cardiac allograft vasculopathy. Eur Heart J. 2011;32:476-484.

3. Andrianov VL, Kamosko MM, Sadof'eva VI, Tikhonenkov ES. The developmental stages of dysplastic coxarthrosis in children (its clinical x-ray characteristics). Ortop Travmatol Protez. 1987:19-23.

4. Libby P, Swanson SJ, Tanaka H, Murray A, Schoen FJ, Pober JS. Immunopathology of coronary arteriosclerosis in transplanted hearts. J Heart Lung Transplant. 1992;11:S5-6.

5. Johnson MR. Transplant coronary disease: nonimmunologic risk factors. J Heart Lung Transplant. 1992;11:S124-132.

6. Grady KL, Costanzo MR, Fisher S, Koch D. Preoperative obesity is associated with decreased survival after heart transplantation. J Heart Lung Transplant. 1996;15:863-871.

7. Gao HZ, Hunt SA, Alderman EL, Liang D, Yeung AC, Schroeder JS. Relation of donor age and preexisting coronary artery disease on angiography and intracoronary ultrasound to later development of accelerated allograft coronary artery disease. J Am Coll Cardiol. 1997;29:623-629.

8. Mangiavacchi M, Frigerio M, Gronda E, Danzi GB, Bonacina E, Masciocco G, Olivia F, De Vita C, Pellegrini A. Acute rejection and cytomegalovirus infection: correlation with cardiac allograft vasculopathy. Transplant Proc. 1995;27:1960-1962.

9. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis. JAMA. 1989;261:3561-3566.

10. Gulizia JM, Kandolf R, Kendall TJ, Thieszen SL, Wilson JE, Radio SJ, Costanzo MR, Winters GL, Miller LL, McManus BM. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts. Am J Pathol. 1995;147:461-475.

11. Ye J, Esmon CT, Johnson AE. The chondroitin sulfate moiety of thrombomodulin binds a second molecule of thrombin. J Biol Chem. 1993;268:2373-9.

12. Doggen CJ, Kunz G, Rosendaal FR, Lane DA, Vos HL, Stubbs PJ, Manger Cats V, Ireland H. A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men. Thromb Haemost. 1998;80:743-8.

13. Norlund L, Zoller B, Ohlin AK. A novel thrombomodulin gene mutation in a patient suffering from sagittal sinus thrombosis. Thromb Haemost. 1997;78:1164-6.

14. Norlund L, Holm J, Zoller B, Ohlin AK. The Ala25-Thr mutation in the thrombomodulin gene is not frequent in Swedish patients suffering from ischemic heart disease. Thromb Haemost. 1999;82:1367-8.

15. Kunz G, Ohlin AK, Adami A, Zoller B, Svensson P, Lane DA. Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function. Blood. 2002;99:3646-53.

16. Salomaa V, Matei C, Aleksic N, Sansores-Garcia L, Folsom AR, Juneja H, Chambless LE, Wu KK.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. 1999;353:1729-34.

17. Conway EM, Pollefeyt S, Collen D, Steiner-Mosonyi M. The amino terminal lectin-like domain of thrombomodulin is required for constitutive endocytosis. Blood. 1997;89:652-61.

18. Zhang Y, Weiler-Guettler H, Chen J, Wilhelm O, Deng Y, Qiu F, Nakagawa K, Klevesath M, Wilhelm S, Bohrer H, Nakagawa M, Graeff H, Martin E, Stern DM, Rosenberg RD, Ziegler R, Nawroth PP. Thrombomodulin modulates growth of tumor cells independent of its anticoagulant activity. J Clin Invest. 1998;101:1301-9.

19. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H, De Vriese A, Weitz JI, Weiler H,Hellings PW, Schaeffer P, Herbert JM, Collen D, Theilmeier G. 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. J Exp Med. 2002;196:565-77.

20. Broze GJ, Jr., Higuchi DA. Coagulation-dependent inhibition of fibrinolysis: role of carboxypeptidase-U and the premature lysis of clots from hemophilic plasma. Blood. 1996;88:3815-23.5. Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol. 2000;20:2511-8.

21. Bajzar L. Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol. 2000;20:2511-8.

22. De Munk GA, Parkinson JF, Groeneveld E, Bang NU, Rijken DC. Role of the glycosaminoglycan component of thrombomodulin in its acceleration of the inactivation of single-chain urokinase-type plasminogen activator by thrombin. Biochem J.1993;290 (Pt 3):655-9.

23. Molinari A, Giorgetti C, Lansen J, Vaghi F, Orsini G, Faioni EM, Mannucci PM. Thrombomodulin is a cofactor for thrombin degradation of recombinant single-chain urokinase plasminogen activator "in vitro" and in a perfused rabbit heart model. Thromb Haemost. 1992;67:226-32.

24. Tohda G, Oida K, Okada Y, Kosaka S, Okada E, Takahashi S, Ishii H, Miyamori I. Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1998;18:1861-1869.

25. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809.

26. Yoshii Y, Okada Y, Sasaki S, Mori H, Oida K, Ishii H. Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences. Med Electron Microsc. 2003;36:165-172.

27. Ireland H, Kunz G, Kyriakoulis K, Stubbs P, Lane DA. Thrombomodulin gene mutations associated with myocardial infarction. Circulation. 1997;96:15-18.

28. Nakazawa F, Koyama T, Shibamiya A, Hirosawa S. Characterization of thrombomodulin gene mutations of the 5’-regulatory region. Atherosclerosis. 2002;164:385-7.

29. Kenneth KW, Nena A, Chul A, Eric B, Aaron RF, Harinder J. Thrombomodulin Ala455Val Polymorphism and Risk of Coronary Heart Disease. Circulation. 2001;103:1386-1389.

30. Li YH, Chen JH, Tsai WC, Chao TH, Guo HR, Tsai LM, Wu HL, Shi GY. Synergistic Effect of Thrombomodulin Promoter -33G/A Polymorphism and Smoking on the Onset of Acute Myocardial Infarction. Thromb Haemost. 2002;87:86–91

31. Chao TH, Li YH, Chen JH, Wu HL, Shi GY, Tsai WC, Chen PS, Liu HL. Relation of Thrombomodulin Gene Polymorphisms to Acute Myocardial Infarction in Patients <50 Years of Age. Am J Cardiol. 2004;93:204-207.

32. Ohnishi Y, Tanaka T, Yamada R, Suematsu K, Minami M, Fujii K, Hoki N, Kodama K, Nagata S, Hayashi T, Kinoshita N, Sato H, Sato H, Kuzuya T, Takeda H, Hori M, Nakamura Y. Identification of 187 single nucleotide polymorphisms (SNPs) among 41 candidate genes for ischemic heart disease in the Japanese population. Hum Genet. 2000;106:288-292.

33. Sugiyama S, Hirota H, Kimura R, Kokubo Y, Kawasaki T, Suehisa E, Okayama A, Tomoike H, Hayashi T, Nishigami K, Kawase I, Miyata T. Haplotype of thrombomodulin gene associated with plasma thrombomodulin level and deep vein thrombosis in the Japanese population. Thromb Res. 2007;119:35-43.

34. Stenina OI, Byzova TV,Adams JC, McCarthy JJ, Topol EJ, Plow EF. Coronary artery disease and the thrombospondin single nucleotide polymorphisms. IJBCB. 2004;36:1013-1030.

35. Auro K, Alanne M, Kristiansson K, Silander K, Kuulasmaa K, Salomaa V, Peltonen L, Perola M. Combined Effects of Thrombosis Pathway Gene Variants Predict Cardiovascular Events. Plos Genet. 2007;3:1244-1253.

36. Park HY, Nabika T, Jang Y, Kwon HM, Cho SY, Masuda J. Association of G-33A Polymorphism in the Thrombomodulin Gene with Myocardial Infarction in Koreans. Hypertens Res. 2002;25:389-394.

37. Auro K, Komulainen K, Alanne M, Silander K, Peltonen L, Perola M, Salomaa V. Thrombomodulin Gene Polymorphisms and Haplotypes and the Risk of Cardiovascular Events: A Prospective Follow-Up Study. Arterioscler Thromb Vasc Biol. 2006;26:942-947.

38. Li J, Pan YC, Li YX. Analysis and application of SNP and haplotype in the human genome. Yichuan Xue Bao. 2005 ;32: 879-889.

39. Suh Y, Vijg J. SNP discovery in associating genetic variation with human disease phenotypes. Mutat Res. 2005;573:41-53.

40. Phillips C. Online resources for SNP analysis: a review and route map. Mol Biotechnol. 2007;35:65-97.

41. Sata M, Saiura A, Nagai R. Hematopoietic stem cells diferentiate into vascular cels that participate in the pathogenesis of athemsclerosis. Nat Med. 2002;8:403-409.

42. Sata M. Circulating vascular progenitor cels contribute to vascular repair, remodeling, and lesion formation. Trends Cardiovasc Med. 2003;13:249-253.

43. Mitchell RN, Libby P. Vascular remodeling in transplant vasculopathy. Circ Res. 2007;100:967-978.

44. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995;75:487-517.

45. Rosenberg E. Backgrounder: recognizing and diagnosing primary HIV infection. Res Initiat Treat Action. 2002;7:5-10.

46. Margariti A, Zeng L, Xu Q. Stem cells, vascular smooth muscle cells and atherosclerosis. Histol Histopathol. 2006;21:979-985.

47. DeRuiter MC, Poelmann RE, VanMunsteren JC, Mironov V, Markwald RR, Gittenberger-de Groot AC. Embryonic endothelial cells transdifferentiate into mesenchymal cells expressing smooth muscle actins in vivo and in vitro. Circ Res. 1997;80:444-451.

48. Frid MG, Kale VA, Stenmark KR. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ Res. 2002;90:1189-1196.

49. Oostrom OV, Fledderus JO, Kleijn DD, Pasterkamp G, Verhaar MC. Smooth Muscle Progenitor Cells: Friend or Foe in Vascular Disease? Curr Stem Cell RES Ther. 2009;4:131-140.

50. Shimizu K, Sugiyama S, Aikawa M, Fukumoto Y, Rabkin E, Libby P, Mitchell RN. Host bone-marrow cells are a source of donor intimal smooth- muscle-like cells in murine aortic transplant arteriopathy. Nat Med. 2001;7:738-741.

51. Li J, Han X, Jiang J, Zhong R, Williams GM, Pickering JG, Chow LH. Vascular smooth muscle cells of recipient origin mediate intimal expansion after aortic allotransplantation in mice. Am J Pathol. 2001;158:1943-1947.

52. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002;8:403-409.

53. Hillebrands JL, Klatter FA, van den Hurk BM, Popa ER, Nieuwenhuis P, Rozing J. Origin of neointimal endothelium and alpha-actin-positive smooth muscle cells in transplant arteriosclerosis. J Clin Invest. 2001;107:1411-1422.

54. Glaser R, Lu MM, Narula N, Epstein JA. Smooth muscle cells, but not myocytes, of host origin in transplanted human hearts. Circulation. 2002;106:17-19.

55. Hruban RH, Long PP, Perlman EJ, Hutchins GM, Baumgartner WA, Baughman KL, Griffin CA. Fluorescence in situ hybridization for the Y-chromosome can be used to detect cells of recipient origin in allografted hearts following cardiac transplantation. Am J Pathol. 1993;142:975-980.

56. Minami E, Laflamme MA, Saffitz JE, Murry CE. Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart. Circulation. 2005;112:2951-2958.

57. Atkinson C, Horsley J, Rhind-Tutt S, Charman S, Phillpotts CJ, Wallwork J, Goddard MJ. Neointimal smooth muscle cells in human cardiac allograft coronary artery vasculopathy are of donor origin. J Heart Lung Transplant. 2004;23:427-435.

58. Simper D, Stalboerger PG, Panetta CJ, Wang S, Caplice NM. Smooth muscle progenitor cells in human blood. Circulation. 2002;106:1199-1204.

59. Sugiyama S, Kugiyama K, Nakamura S, Kataoka K, Aikawa M, Shimizu K, Koide S, Mitchell RN, Ogawa H, Libby P. Characterization of smooth muscle-like cells in circulating human peripheral blood. Atherosclerosis. 2006;187:351-362.

60. Deb A, Skelding KA, Wang S, Reeder M, Simper D, Caplice NM. Integrin profile and in vivo homing of human smooth muscle progenitor cells. Circulation. 2004;110:2673-2677.

61. Conway, EM, Van de Wouwer, M, Pollefeyt, S, Jurk, K, Van Aken, H, De Vriese, A, 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. J Exp Med. 2002;196:565-77.

62. Uchiba, M, Okajima, K, Murakami, K, Johno, M, Mohri, M, Okabe, H, et al. rhs-TM prevents ET-induced increase in pulmonary vascular permeability through protein C activation. Am J Physiol. 1997;273:L889-94.

63. Mohri, M, Suzuki, M, Sugimoto, E, Sata, M, Yamamoto, S and Maruyama, I. Effects of recombinant human soluble thrombomodulin (rhs-TM) on clot-induced coagulation in human plasma. Thromb Haemost. 1998;80:925-9.

64. Esmon, CT. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. J Exp Med. 2002;196:561-4.

65. Day JD, Rayburn BK, Gaudin PB, et al. Cardiac allograft vasculopathy: the central pathogenetic role of ischemia-induced endothelial cell injury. J Heart Lung Transplant. 1995;14:S142-9.

66. Burns WR, Wang Y, Tang PC, et al. Recruitment of CXCR3+ and CCR5+ T cells and production of interferon-gamma-inducible chemokines in rejecting human arteries. Am J Transplant. 2005;5:1226-36.

67. Minami K, Murata K, Lee CY, et al. C4d deposition and clearance in cardiac transplants correlates with alloantibody levels and rejection in rats. Am J Transplant. 2006;6:923-32.

68. Wehner J, Morrell CN, Reynolds T, et al. Antibody and complement in transplant vasculopathy. Circ Res. 2007;100:191-203.

69. Celi A, Pellegrini G, Lorenzet R, et al. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A. 1994;91:8767-71.

70. Weyrich AS, McIntyre TM, McEver RP, et al. Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest. 1995;95:2297-303.

71. Suzuki K, Kusumoto H, Deyashiki Y, et al. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J. 1987;6:1891-7.

72. Koutsi A, Papapanagiotou A, Papavassiliou AG. Thrombomodulin: from haemostasis to inflammation and tumourigenesis. Int J Biochem Cell Biol. 2008;40:1669-73.

73. Weiler H, Isermann BH. Thrombomodulin. J Thromb Haemost. 2003;1:1515-24.

74. MacGregor IR, Perrie AM, Donnelly SC, et al. Modulation of human endothelial thrombomodulin by neutrophils and their release products. Am J Respir Crit Care Med. 1997;155:47-52.

75. Welters I, Menges T, Ballesteros M, et al. Thrombin generation and activation of the thrombomodulin protein C system in open heart surgery depend on the underlying cardiac disease. Thromb Res. 1998;92:1-9.

76. Van de Wouwer M, Plaisance S, De Vriese A, et al. The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis. J Thromb Haemost. 2006;4:1813-24.

77. Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:345-57.

78. Ohlin AK, Marlar RA. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood. 1995;85:330-6.

79. Le Flem L, Picard V, Emmerich J, et al. Mutations in promoter region of thrombomodulin and venous thromboembolic disease. Arterioscler Thromb Vasc Biol. 1999;19:1098-104.

80. Ohlin AK, Norlund L, Marlar RA. Thrombomodulin gene variations and thromboembolic disease. Thromb Haemost. 1997;78:396-400.

81. Sugiyama S, Hirota H, Kimura R, et al. Haplotype of thrombomodulin gene associated with plasma thrombomodulin level and deep vein thrombosis in the Japanese population. Thromb Res. 2007;119:35-43.

82. Norlund L, Holm J, Zoller B, et al. A common thrombomodulin amino acid dimorphism is associated with myocardial infarction. Thromb Haemost. 1997;77:248-51.

83. Thude H, Wilkens A, Anders O, et al. Analysis of the thrombomodulin gene in patients with venous thrombosis. Thromb Res. 2002;107:109-14.

84. Aleksic N, Folsom AR, Cushman M, et al. Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study. J Thromb Haemost. 2003;1:88-94.

85. Hillebrands JL, Klatter FA, Rozing J. Origin of vascular smooth muscle cells and the role of circulating stem cells in transplant arteriosclerosis. Arterioscler Thromb Vasc Biol. 2003;23:380-7.

86. Hu Y, Davison F, Zhang Z, et al. Endothelial replacement and angiogenesis in arteriosclerotic lesions of allografts are contributed by circulating progenitor cells. Circulation. 2003;108:3122-7.

87. Tsai CS, Tsai YT, Lin CY, et al. Expression of thrombomodulin on monocytes is associated with early outcomes in patients with coronary artery bypass graft surgery. Shock. 2010;34:31-9.

88. David S, Paul G. S, Carmelo J. P, Shaohua W, Noel M. Smooth Muscle Progenitor Cells in Human Blood. Circulation. 2002;106:41-46.

89. Owens G, Kumar M, Wamhof B, et a1. Molecular regulation of vascular smooth muscle cell difierentiation in development of diseases. Physiol Re. 2004;84:767 -801.

90. Xu Q. I1he impact of progenitor cels in atherosclerosis. Nat Clin Pract Cardiovasc Med. 2006;3;94-101.

91. Deb A, Skelding KA, Caplice NM, et a1. Integin profile and in vivo homing of human smooth muscle progenitor cells. Circulation. 2004;110:2673-2677.

92. George T, Jordan SP. Interferon-γ Axis in Graft Arteriosclerosis. Circ Res. 2007;100:622-632.

93. John AB, Abbas A. Chemokines and transplant vasculopathy. Circ Res. 2008;103:454-466.

94. Bustin M. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci. 2000;26:152-153.

95. Stros M, Cherny D, Jivin TM. HMG-1 protein stimulates DNA end joining by promoting association of DNA molecules via their via their ends. Eur J Biochem. 2000;367:4088-4097.

96. Bustin M, Lehn DA, Landsman D. Structual features of the HMG chromosomal proteins and their genes. Biochem Biophys Acta. 1990;1049:231-243.

97. Bentley DR, Delouk BP, Dunham A, et al. The physical maps for sequencing human chromosomes 1, 6, 9, 10, 13, 20 and X. Nature. 2001;409:942-943.

98. Lum HK, Lee KL. The human HMGB1 promoter is modulated by a silencer and an enhancer-containing intron. Biochim Biophys Acts. 2001;1520:79-84.

99. Li J, Kokkola R, Tabibzadeh S, et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol Med. 2003;9:37-45.

100. Melvin VS, Edwards DP. Coregulatory proteins in steroid hormone receptor action:the role of chromatin high mobility group proteins HMGB-1 and-2. Steroids. 1999:64:576-586.

101. Shingo Y, Ikuro M. HMGB1, a novel inflammatory cytokine. Clinica Chimica Acta. 2007;375:36–42.

102. Oozawa S, Mori S, Kanke T, Takahashi H, Liu K, Tomono Y, Asanuma M, Miyazaki I, Nishibori M, Sano S. Effects of HMGB1 on ischemia reperfusion injury in the rat heart. Circulation. 2008;72:1178-1184.

103. Martin A, Hans CV, John CI, Benjamin F, Sebastian NE, Sebastian B, Frank A, Sven TP, Ivan KL, Florian B, Stefan EH, Per MH, Marco EB, Heimo M, Peter PN, Andrew R, Hugo AK, Angelika B. High mobility group Box 1 in ischemia reperfusion injury of the heart. Circulation. 2008;117:3216-3226.

104. Kalinina N, Agrotis A, Antropova Y, DiVitto G, Kanellakis P, Kostolias G, Ilyinskaya O, Tararak E, Bobik A. Increased expression of the DNA binding cytokine HMGB1 in human atherosclerotic lesions:role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol. 2004;24:2320-2325.

105. Inoue K, Kawahara K, Biswas KK, Ando K, Mitsudo K, Nobuyoshi M, Maruyama I. HMGB1 expression by activated vascular smooth muscle cells in advanced human atherosclerosis plaques. Cardiovasc Pathol. 2007;16:136-143.

106. Kazuhiro A, David MS, Yuji I, Kawahara1 KI, Yasushi Y, Motoyuki T, Tomonori U, Nobuo I, Yoshiaki Y, Shingo Y, Yasuhiko Y, Hiroshi Y, Satoshi I, Noboru T and Ikuro M. The N-terminal domain of thrombomodulin sequesters high mobility group B1 protein, a novel antiinflammatory mechanism. Clin Invest. 2005;115:1267-1274.

107. Takeno M, Yasuda S, Otsuka Y, Morii I, Kawamura A, Yano K, Miyazaki S. Impact of metabolic syndrome on the long term survival of patients with acute myocardial infarction. Circulation. 2008;72:415-419.

108. Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK. HMGB1,a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci. 2006;26:6413-6421.

109. Limana F, Germani A, Zacheo A, Kajstura J, Di Carlo A, Borsellino G, Leoni O, Palumbo R, Battistini L, Rastaldo R, Muller S, Pompilio G, Anversa P, Bianchi ME, Capogrossi MC. Exogenous high-mobility group box 1 protein induces myocardial regeneration after infarction via enhanced cardiac C-kit+ cell proliferation and differentiation. Circ Res. 2005;97:e73-83.
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