請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77045完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊鎧鍵(Kai-Chien Yang) | |
| dc.contributor.author | Pei-Chen Wu | en |
| dc.contributor.author | 吳佩蓁 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:44:31Z | - |
| dc.date.available | 2021-07-10T21:44:31Z | - |
| dc.date.copyright | 2020-09-10 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-07-16 | |
| dc.identifier.citation | 1. Andrade J, Khairy P, Dobrev D and Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res. 2014;114:1453-68. doi:10.1161/CIRCRESAHA.114.303211. 2. Heijman J, Voigt N and Dobrev D. New directions in antiarrhythmic drug therapy for atrial fibrillation. Future Cardiol. 2013;9:71-88. doi:10.2217/fca.12.78. 3. Lip GYH, Brechin CM and Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest. 2012;142:1489-1498. doi:10.1378/chest.11-2888. 4. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA and Benjamin EJ. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:1042-6. doi:10.1161/01.CIR.0000140263.20897.42. 5. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Herpen G, Stricker BH, Stijnen T, Lip GY and Witteman JC. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J. 2006;27:949-53. doi:10.1093/eurheartj/ehi825. 6. Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P and Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-66. doi:10.1056/NEJM199809033391003. 7. Kottkamp H, Schreiber D, Moser F and Rieger A. Therapeutic Approaches to Atrial Fibrillation Ablation Targeting Atrial Fibrosis. JACC Clin Electrophysiol. 2017;3:643-653. doi:10.1016/j.jacep.2017.05.009. 8. Xintarakou A, Tzeis S, Psarras S, Asvestas D and Vardas P. Atrial fibrosis as a dominant factor for the development of atrial fibrillation: facts and gaps. Europace. 2020;22:342-351. doi:10.1093/europace/euaa009. 9. Yue L, Xie J and Nattel S. Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc Res. 2011;89:744-53. doi:10.1093/cvr/cvq329. 10. Zlochiver S, Munoz V, Vikstrom KL, Taffet SM, Berenfeld O and Jalife J. Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias in two-dimensional cardiac monolayers. Biophys J. 2008;95:4469-80. doi:10.1529/biophysj.108.136473. 11. Nattel S. How does fibrosis promote atrial fibrillation persistence: in silico findings, clinical observations, and experimental data. Cardiovasc Res. 2016;110:295-7. doi:10.1093/cvr/cvw092. 12. Spach MS, Dolber PC and Heidlage JF. Influence of the passive anisotropic properties on directional differences in propagation following modification of the sodium conductance in human atrial muscle. A model of reentry based on anisotropic discontinuous propagation. Circ Res. 1988;62:811-32. doi:10.1161/01.res.62.4.811. 13. Miragoli M, Salvarani N and Rohr S. Myofibroblasts induce ectopic activity in cardiac tissue. Circ Res. 2007;101:755-8. doi:10.1161/CIRCRESAHA.107.160549. 14. Vasquez C, Mohandas P, Louie KL, Benamer N, Bapat AC and Morley GE. Enhanced fibroblast-myocyte interactions in response to cardiac injury. Circ Res. 2010;107:1011-20. doi:10.1161/CIRCRESAHA.110.227421. 15. Kaur K, Zarzoso M, Ponce-Balbuena D, Guerrero-Serna G, Hou L, Musa H and Jalife J. TGF-beta1, released by myofibroblasts, differentially regulates transcription and function of sodium and potassium channels in adult rat ventricular myocytes. PLoS One. 2013;8:e55391. doi:10.1371/journal.pone.0055391. 16. Lijnen PJ, Petrov VV and Fagard RH. Induction of cardiac fibrosis by transforming growth factor-beta(1). Mol Genet Metab. 2000;71:418-35. doi:10.1006/mgme.2000.3032. 17. Burstein B and Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51:802-9. doi:10.1016/j.jacc.2007.09.064. 18. Nakajima H, Nakajima HO, Salcher O, Dittie AS, Dembowsky K, Jing S and Field LJ. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res. 2000;86:571-9. doi:10.1161/01.res.86.5.571. 19. Verheule S, Sato T, Everett Tt, Engle SK, Otten D, Rubart-von der Lohe M, Nakajima HO, Nakajima H, Field LJ and Olgin JE. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-beta1. Circ Res. 2004;94:1458-65. doi:10.1161/01.RES.0000129579.59664.9d. 20. Dobrev D and Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet. 2010;375:1212-23. doi:10.1016/S0140-6736(10)60096-7. 21. Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ, Jr., Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Iesaka Y, Jackman W, Jalife J, Jais P, Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, Lindsay BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM and Wilber D. 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Europace. 2012;14:528-606. doi:10.1093/europace/eus027. 22. Nagaraju CK, Robinson EL, Abdesselem M, Trenson S, Dries E, Gilbert G, Janssens S, Van Cleemput J, Rega F, Meyns B, Roderick HL, Driesen RB and Sipido KR. Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure. J Am Coll Cardiol. 2019;73:2267-2282. doi:10.1016/j.jacc.2019.02.049. 23. Fang L, Murphy AJ and Dart AM. A Clinical Perspective of Anti-Fibrotic Therapies for Cardiovascular Disease. Front Pharmacol. 2017;8:186. doi:10.3389/fphar.2017.00186. 24. Horna-Terron E, Pradilla-Dieste A, Sanchez-de-Diego C and Osada J. TXNDC5, a newly discovered disulfide isomerase with a key role in cell physiology and pathology. Int J Mol Sci. 2014;15:23501-18. doi:10.3390/ijms151223501. 25. Kojima R, Okumura M, Masui S, Kanemura S, Inoue M, Saiki M, Yamaguchi H, Hikima T, Suzuki M, Akiyama S and Inaba K. Radically different thioredoxin domain arrangement of ERp46, an efficient disulfide bond introducer of the mammalian PDI family. Structure. 2014;22:431-43. doi:10.1016/j.str.2013.12.013. 26. Zhang L, Hou Y, Li N, Wu K and Zhai J. The influence of TXNDC5 gene on gastric cancer cell. J Cancer Res Clin Oncol. 2010;136:1497-505. doi:10.1007/s00432-010-0807-x. 27. Wang Y, Ma Y, Lu B, Xu E, Huang Q and Lai M. Differential expression of mimecan and thioredoxin domain-containing protein 5 in colorectal adenoma and cancer: a proteomic study. Exp Biol Med (Maywood). 2007;232:1152-9. doi:10.3181/0701-RM-8. 28. Wang L, Song G, Chang X, Tan W, Pan J, Zhu X, Liu Z, Qi M, Yu J and Han B. The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway. Oncogene. 2015;34:4735-45. doi:10.1038/onc.2014.401. 29. Shih YC, Chen CL, Zhang Y, Mellor RL, Kanter EM, Fang Y, Wang HC, Hung CT, Nong JY, Chen HJ, Lee TH, Tseng YS, Chen CN, Wu CC, Lin SL, Yamada KA, Nerbonne JM and Yang KC. Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation. Circ Res. 2018;122:1052-1068. doi:10.1161/CIRCRESAHA.117.312130. 30. Wu YF, Wang CY, Yang TL, Tsao PN, Lin SJ and Tan HY. Intravital multi-photon microscopic imaging platform for ocular surface imaging. Exp Eye Res. 2019. doi:10.1016/j.exer.2019.02.016. 31. Wu YF, Tan HY and Lin SJ. Long-Term Intravital Imaging of the Cornea, Skin, and Hair Follicle by Multiphoton Microscope. Methods Mol Biol. 2019. doi:10.1007/7651_2019_227. 32. Mitchell GF, Jeron A and Koren G. Measurement of heart rate and Q-T interval in the conscious mouse. Am J Physiol. 1998;274:H747-51. doi:10.1152/ajpheart.1998.274.3.H747. 33. Zheng YB, Xiao YY, Tan P, Zhang Q and Xu P. Live-cell visualization of intracellular interaction between a nuclear migration protein (hNUDC) and the thrombopoietin receptor (Mpl). PLoS One. 2012;7:e51849. doi:10.1371/journal.pone.0051849. 34. Karpova TS, Baumann CT, He L, Wu X, Grammer A, Lipsky P, Hager GL and McNally JG. Fluorescence resonance energy transfer from cyan to yellow fluorescent protein detected by acceptor photobleaching using confocal microscopy and a single laser. J Microsc. 2003;209:56-70. doi:10.1046/j.1365-2818.2003.01100.x. 35. Yeh YH, Kuo CT, Lee YS, Lin YM, Nattel S, Tsai FC and Chen WJ. Region-specific gene expression profiles in the left atria of patients with valvular atrial fibrillation. Heart Rhythm. 2013;10:383-91. doi:10.1016/j.hrthm.2012.11.013. 36. Dobrev D, Aguilar M, Heijman J, Guichard JB and Nattel S. Postoperative atrial fibrillation: mechanisms, manifestations and management. Nat Rev Cardiol. 2019;16:417-436. doi:10.1038/s41569-019-0166-5. 37. Li JY, Lai YJ, Yeh HI, Chen CL, Sun S, Wu SJ and Lin FY. Atrial gap junctions, NF-kappaB and fibrosis in patients undergoing coronary artery bypass surgery: the relationship with postoperative atrial fibrillation. Cardiology. 2009;112:81-8. doi:10.1159/000141012. 38. Muller P, Hars C, Schiedat F, Bosche LI, Gotzmann M, Strauch J, Dietrich JW, Vogt M, Tannapfel A, Deneke T, Mugge A and Ewers A. Correlation between total atrial conduction time estimated via tissue Doppler imaging (PA-TDI Interval), structural atrial remodeling and new-onset of atrial fibrillation after cardiac surgery. J Cardiovasc Electrophysiol. 2013;24:626-31. doi:10.1111/jce.12084. 39. Tinica G, Mocanu V, Zugun-Eloae F and Butcovan D. Clinical and histological predictive risk factors of atrial fibrillation in patients undergoing open-heart surgery. Exp Ther Med. 2015;10:2299-2304. doi:10.3892/etm.2015.2790. 40. Sun W, Chang S, Tai DC, Tan N, Xiao G, Tang H and Yu H. Nonlinear optical microscopy: use of second harmonic generation and two-photon microscopy for automated quantitative liver fibrosis studies. J Biomed Opt. 2008;13:064010. doi:10.1117/1.3041159. 41. Yata Y, Scanga A, Gillan A, Yang L, Reif S, Breindl M, Brenner DA and Rippe RA. DNase I-hypersensitive sites enhance alpha1(I) collagen gene expression in hepatic stellate cells. Hepatology. 2003;37:267-76. doi:10.1053/jhep.2003.50067. 42. Buck TM, Wright CM and Brodsky JL. The activities and function of molecular chaperones in the endoplasmic reticulum. Semin Cell Dev Biol. 2007;18:751-61. doi:10.1016/j.semcdb.2007.09.001. 43. Cucoranu I, Clempus R, Dikalova A, Phelan PJ, Ariyan S, Dikalov S and Sorescu D. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005;97:900-7. doi:10.1161/01.RES.0000187457.24338.3D. 44. Matsuzawa A and Ichijo H. Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochim Biophys Acta. 2008;1780:1325-36. doi:10.1016/j.bbagen.2007.12.011. 45. Fernandes DC, Manoel AH, Wosniak J, Jr. and Laurindo FR. Protein disulfide isomerase overexpression in vascular smooth muscle cells induces spontaneous preemptive NADPH oxidase activation and Nox1 mRNA expression: effects of nitrosothiol exposure. Arch Biochem Biophys. 2009;484:197-204. doi:10.1016/j.abb.2009.01.022. 46. Trevelin SC and Lopes LR. Protein disulfide isomerase and Nox: new partners in redox signaling. Curr Pharm Des. 2015;21:5951-63. doi:10.2174/1381612821666151029112523. 47. Liu Z, Li C, Kang N, Malhi H, Shah VH and Maiers JL. Transforming growth factor beta (TGFbeta) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J Biol Chem. 2019;294:3137-3151. doi:10.1074/jbc.RA118.005761. 48. Tanjore H, Lawson WE and Blackwell TS. Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochim Biophys Acta. 2013;1832:940-7. doi:10.1016/j.bbadis.2012.11.011. 49. Vekich JA, Belmont PJ, Thuerauf DJ and Glembotski CC. Protein disulfide isomerase-associated 6 is an ATF6-inducible ER stress response protein that protects cardiac myocytes from ischemia/reperfusion-mediated cell death. J Mol Cell Cardiol. 2012;53:259-67. doi:10.1016/j.yjmcc.2012.05.005. 50. Everett THt and Olgin JE. Atrial fibrosis and the mechanisms of atrial fibrillation. Heart Rhythm. 2007;4:S24-7. doi:10.1016/j.hrthm.2006.12.040. 51. Kong P, Christia P and Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014;71:549-74. doi:10.1007/s00018-013-1349-6. 52. Tan AY and Zimetbaum P. Atrial fibrillation and atrial fibrosis. J Cardiovasc Pharmacol. 2011;57:625-9. doi:10.1097/FJC.0b013e3182073c78. 53. Jalife J and Kaur K. Atrial remodeling, fibrosis, and atrial fibrillation. Trends Cardiovasc Med. 2015;25:475-84. doi:10.1016/j.tcm.2014.12.015. 54. Thanigaimani S, Lau DH, Agbaedeng T, Elliott AD, Mahajan R and Sanders P. Molecular mechanisms of atrial fibrosis: implications for the clinic. Expert Rev Cardiovasc Ther. 2017;15:247-256. doi:10.1080/14779072.2017.1299005. 55. Wynn TA and Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028-40. doi:10.1038/nm.2807. 56. Gourdie RG, Dimmeler S and Kohl P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat Rev Drug Discov. 2016;15:620-638. doi:10.1038/nrd.2016.89. 57. Brunner AM, Marquardt H, Malacko AR, Lioubin MN and Purchio AF. Site-directed mutagenesis of cysteine residues in the pro region of the transforming growth factor beta 1 precursor. Expression and characterization of mutant proteins. J Biol Chem. 1989;264:13660-4. 58. Ponticos M, Harvey C, Ikeda T, Abraham D and Bou-Gharios G. JunB mediates enhancer/promoter activity of COL1A2 following TGF-beta induction. Nucleic Acids Res. 2009;37:5378-89. doi:10.1093/nar/gkp544. 59. Nakajima H, Nakajima HO, Dembowsky K, Pasumarthi KB and Field LJ. Cardiomyocyte cell cycle activation ameliorates fibrosis in the atrium. Circ Res. 2006;98:141-8. doi:10.1161/01.RES.0000197783.70106.4a. 60. Platonov PG, Mitrofanova LB, Orshanskaya V and Ho SY. Structural abnormalities in atrial walls are associated with presence and persistency of atrial fibrillation but not with age. J Am Coll Cardiol. 2011;58:2225-32. doi:10.1016/j.jacc.2011.05.061. 61. Lubitz SA, Yin X, Rienstra M, Schnabel RB, Walkey AJ, Magnani JW, Rahman F, McManus DD, Tadros TM, Levy D, Vasan RS, Larson MG, Ellinor PT and Benjamin EJ. Long-term outcomes of secondary atrial fibrillation in the community: the Framingham Heart Study. Circulation. 2015;131:1648-55. doi:10.1161/CIRCULATIONAHA.114.014058. 62. Greenberg JW, Lancaster TS, Schuessler RB and Melby SJ. Postoperative atrial fibrillation following cardiac surgery: a persistent complication. Eur J Cardiothorac Surg. 2017;52:665-672. doi:10.1093/ejcts/ezx039. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77045 | - |
| dc.description.abstract | 心房顫動(atrial fibrillation, AF)是成人最常見的心律不整之一，會造成心輸出量下降及在心房或心耳形成血栓，繼而引發心臟衰竭、中風或器官栓塞，使得心血管功能惡化或甚死亡的風險大增。AF的風險會隨著年紀增長而逐漸上升，由於全球人口老化加速，AF的發生率與盛行率都明顯增加。目前針對AF的有效治療十分有限，多半以控制心跳及減少栓塞風險為主，仍需要針對AF本身的致病機轉深入研究，才能找出新型預防及治療AF的策略。目前對於心房顫動形成的機轉的認知，是一連串複雜的心房結構與電生理功能異常所組成，但這些異常變化的分子機轉，仍存在許多未知，亟需深入探討研究。許多研究已經指出，心房纖維化在心房結構與電生理功能異常上具有重要角色，是造成心房顫動發生的重要關鍵之一。相較於心室，心房更容易在受到病理性刺激時，產生纖維化，進而誘發心律不整。因此，找出引起心房纖維化的致病分子機轉，是發展新型AF治療方向的重要關鍵。我們的研究團隊，最近發現一個內質網蛋白—硫氧還原蛋白5(thioredoxin domain containing 5，TXNDC5)在心臟衰竭與心室纖維化上有重要角色，因此本實驗想探討TXNDC5在心房纖維化及AF所扮演的角色。首先，我們發現在相較於正常心律(normal sinus rhythm)的病人心房組織，AF病人心房組織有較高表現的TXNDC5。進一步的實驗也證實，TXNDC5上升會促進心房纖維母細胞的活化增生及ECM的製造。研究結果也顯示，TXNDC5 會透過自身的蛋白雙硫鍵異構酶 (protein disulfide isomerase) 活性，造成活性氧類 (reactive oxygen species，ROS)上升，進而活化c-Jun N末端激酶(JNK)從而促進心房纖維母細胞的活化與增生及ECM蛋白的產生。而乙型轉化生長因子（transforming growth factor beta, TGF-β）會透過內質網壓力(endoplasmic reticulum stress，ER stress)活化下游的轉錄因子並促進TXNDC5的上升。最後，將小鼠纖維母細胞中的TXNDC5基因剔除後，能減輕小鼠心房纖維化及電刺激誘發AF的頻率。這些實驗結果顯示TXNDC5在心房纖維化與心房顫動的發生確實扮演十分重要的角色，並且有機會能作為心房纖維化與心房顫動的有效治療策略。 | zh_TW |
| dc.description.abstract | Introduction: Atrial fibrosis, a hallmark of atrial fibrillation (AF), provides substrates to initiate/propagate fibrillation waves in the atria. We have recently identified an endoplasmic reticulum (ER) protein thioredoxin domain containing 5 (TXNDC5) as a critical mediator of cardiac ventricular fibrosis. We hypothesized that TXNDC5 could also play an important role in the pathogenesis of atrial fibrosis and fibrillation. Methods: RNA sequencing was performed on the atrial samples from patients undergoing open-heart surgery with normal sinus rhythm or AF. TXNDC5 and extracellular matrix (ECM) expression were quantified by quantitative PCR and western blotting in human atrial fibroblasts (hAF). Additionally, TXNDC5 was globally (Txndc5-/-) or conditionally (Txndc5fl/fl; Col1a2-Cre/ERT2) knocked out in a transgenic mouse model (a-MHC-TGFβ cys33ser), which develop extensive atrial fibrosis and inducible AF. Masson's trichrome and picrosirius red staining were used to analyze fibrotic tissue area. AF inducibility was assessed by transesophageal atrial stimulation. Results: TXNDC5 expression levels were significantly upregulated in the atrial tissue from patients with AF, and were positively correlated with those of transcripts encoding transforming growth factor β1 (TGFβ1) and ECM proteins in human atrial tissue. TXNDC5 is required for TGFβ1-induced fibroblast activation, proliferation, and ECM production. Also, elevated TXNDC5 expression level is sufficient to trigger these fibrogenic effects through c-Jun N-terminal kinase (JNK) signaling mediated by PDI activity of TXNDC5. In vivo study showed that global or conditional deletion of TXNDC5 in a-MHC-TGFβcys33ser mice considerably mitigated the extent of atrial fibrosis. Lastly, transesophageal atrial burst pacing induced AF 83% (5 out of 6) in a-MHC-TGFcys33ser mice, whereas conditional TXNDC5 knockout markedly reduced the inducibility of AF (22%, 2 out of 9) in a-MHC-TGFcys33ser mice. Conclusion: TXNDC5 augments atrial fibrosis by promoting cardiac fibroblast proliferation and ECM protein production via JNK signaling activation. Targeted deletion of Txndc5 protects against TGFβ induced atrial fibrosis and AF. Thus, TXNDC5 could be a new therapeutic target for atrial fibrosis and fibrillation. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:44:31Z (GMT). No. of bitstreams: 1 U0001-1507202015455100.pdf: 4296396 bytes, checksum: 576c997e8e59b7f0e49868242d4b2f61 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 口試委員審定書 i 中文摘要 ii ABSTRACT iv CONTENTS vi LIST OF FIGURES ix Chapter 1 Introduction 1 1.1 Atrial fibrillation: the most common cardiac arrhythmia 1 1.2 Mechanism underlying atrial fibrillation 1 1.3 TGFβ1 in fibroblasts in atrial fibrosis 2 1.4 Limitation in current AF management 2 1.5 TXNDC5 3 Chapter 2 Materials and Methods 4 2.1 Human tissue samples 4 2.2 Experimental animals 4 2.3 Murine primary atrial fibroblasts (mAF) isolation 5 2.4 Histology and immunohistochemical staining (IHC) 5 2.5 Immunofluorescence (IF) 6 2.6 Multi-photon microscopy and second-harmonic generation (SHG) imaging 7 2.7 Hydroxyproline assay 7 2.8 Electrophysiological recording 7 2.9 Programmed electrical stimulation 8 2.10 Human primary atrial fibroblast (hAF) culture 9 2.11 Lentiviral transduction 9 2.12 RNA extraction and qRT-PCR 9 2.13 Cellular ROS detection assay 10 2.14 Immunoblot analysis 10 2.15 Fibroblasts proliferation assay 11 2.16 TXNDC5 promoter luciferase activity assay 11 2.17 Generation of TXNDC5 AAA mutant lacking PDI activity 12 2.18 Immunoprecipitation (IP) 12 2.19 FRET (fluorescence resonance energy transfer) based protein folding assay 13 2.20 List of pharmacological inhibitors and concentrations used in the present study 14 2.21 Statistical analysis 14 Chapter 3 Results 15 3.1 TXNDC5 upregulation is accompanied by increased TGFβ1 and fibrosis markers in AF patients 15 3.2 Txndc5 depletion protects against TGFβ1–induced atrial fibrosis 16 3.3 TXNDC5 is enriched in atrial fibroblasts and upregulated in response to TGFβ1 17 3.4 TXNDC5 regulates atrial fibroblasts activation, proliferation, and ECM production 18 3.5 TXNDC5 facilitates ECM protein folding in hAF 19 3.6 TXNDC5 provokes hAF activation through JNK pathway 20 3.7 TXNDC5 activates JNK via PDI-derived reactive oxygen species (ROS) 21 3.8 TGF-β1 induces TXNDC5 upregulation through elevation of ER stress and activation of Transcription Factor 6 (ATF6) 22 3.9 Inducible fibroblast-specific Txndc5 Ablation attenuates atrial fibrosis and burden of atrial fibrillation 23 Chapter 4 Discussion 25 4.1 TXNDC5 as a novel target for atrial fibrosis and AF 25 4.2 Upregulation of TXNDC5 specifically in fibroblasts 25 4.3 Therapeutic potential of TXNDC5 ablation in vivo 26 4.4 Clinical perspective of targeting TXNDC5 27 REFERENCE 29 FIGURES AND TABLES 38 | |
| dc.language.iso | en | |
| dc.subject | 乙型轉化生長因子 | zh_TW |
| dc.subject | 硫氧還原蛋白5 | zh_TW |
| dc.subject | 心房顫動 | zh_TW |
| dc.subject | 心房纖維化 | zh_TW |
| dc.subject | 心房纖維母細胞 | zh_TW |
| dc.subject | atrial fibrosis | en |
| dc.subject | TXNDC5 | en |
| dc.subject | TGFβ1 | en |
| dc.subject | atrial fibroblast | en |
| dc.subject | atrial fibrillation | en |
| dc.title | 內質網蛋白TXNDC5在心房纖維化及心房顫動的角色 | zh_TW |
| dc.title | Role of ER Protein TXNDC5 in the Pathogenesis of Atrial Fibrosis and Fibrillation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳文彬(Wen-Pin Chen),葉勇信(Yung-Hsin Yen),胡瑜峰(Yu-Feng Hu) | |
| dc.subject.keyword | 硫氧還原蛋白5,心房顫動,心房纖維化,心房纖維母細胞,乙型轉化生長因子, | zh_TW |
| dc.subject.keyword | TXNDC5,atrial fibrosis,atrial fibrillation,atrial fibroblast,TGFβ1, | en |
| dc.relation.page | 63 | |
| dc.identifier.doi | 10.6342/NTU202001546 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-07-16 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-1507202015455100.pdf 未授權公開取用 | 4.2 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。