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系統識別號 U0026-0108201414242500
論文名稱(中文) 細胞外基質蛋白CCN1調控心肌細胞之細胞凋亡與細胞自噬
論文名稱(英文) Extracellular Matrix Protein CCN1 Regulates Apoptosis and Autophagy in Cardiomyocytes
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 蘇柏全
研究生(英文) Bor-Chyuan Su
學號 s58981434
學位類別 博士
語文別 英文
論文頁數 77頁
口試委員 召集委員-林以行
口試委員-劉校生
口試委員-蔣輯武
指導教授-莫凡毅
口試委員-鄭敬楓
口試委員-戴明泓
中文關鍵字 心肌細胞  心肌母細胞  細胞凋亡  細胞自噬 
英文關鍵字 Cardiomyocytes  cardiomyoblasts  apoptosis  autophagy 
學科別分類
中文摘要 心臟是一個再生能力相當有限的器官,但是最近的研究發現,在心臟中有一小部份的心肌細胞仍然具有增生的能力,且在正常的心臟的恆定及面臨心臟受損時,這群細胞提供新的心肌細胞主要來源。探討不具增生能力(postmitotic)及具有增生能力之心肌細胞對於細胞死亡之調控,可針對其不同之特性來開發治療心臟受損之藥物。而Fas/Fas ligand(FasL)參與在許多心臟疾病中,但是具活化Fas功能之抗體Jo2卻無法在體內造成心肌細胞凋亡,暗示著有其他的因子參與在調控Fas所誘發之細胞凋亡。細胞外基質蛋白CCN1可以促進FasL對於人類皮膚纖維母細胞之細胞毒性的能力。CCN1也被誘發表現於多種的心臟病變。因此我們推測 CCN1和FasL也許會共同調控心肌細胞的存活。我們發現CCN1和FasL會透過不同的機制協同性的刺激不具增生能力之心肌細胞和H9c2心肌母細胞(具有增生能力之心肌細胞)進行細胞凋亡。在初級心肌細胞CCN1透過活性氧化物質和p38去增加細胞表面的Fas受體,使得細胞對於FasL所誘發的凋亡較為敏感。然而在H9c2細胞,CCN1則是透過增加細胞質中的Smac和HtrA2去拮抗XIAP之抗凋亡作用來增強FasL心毒性。再者,我們也發現保護性的細胞自噬會被誘發來限制CCN1之心毒性。整體而言,CCN1在心臟受損中扮演一個有害的角色,因為CCN1會讓心肌細胞對於FasL造成之細胞毒性較為敏感。CCN1或許可以是治療壓力所造成之心臟受損新的治療標的。
英文摘要 Mammalian hearts are with limited regenerative capacity. Recent studies demonstrated that a small portion of resident cardiomyocytes possesses proliferative ability, which is the major source of cardiomyocyte renewal in myocardial homeostasis and in myocardial injury. Understanding the regulation of cell apoptosis on the postmitotic and proliferative cardiomyocytes can provide insights and leads to discover potential therapeutic targets for myocardial injury. Among the physiological regulators, Fas/Fas ligand (FasL) are implicated in various cardiac pathological conditions; however, Fas agonistic antibody Jo2 is unable to induce cardiomyocyte apoptosis in vivo, suggesting that additional factors are required in the regulation of Fas-mediated apoptosis. Extracellular protein CCN1 has been demonstrated to promote cytotoxicity of FasL in human skin fibroblasts. In addition, CCN1 is induced in a variety of cardiac pathologies. We hypothesized that CCN1 and FasL may coordinatively regulate cardiomyocyte survival. We found that CCN1 and FasL synergized to induce primary cardiomyocyte (postmitotic cardiomyocyte) and H9c2 cardiomyoblast (proliferative cardiomyocyte) apoptosis via distinct mechanisms. CCN1 sensitized primary cardiomyocytes to FasL-induced apoptosis through inducing ROS and the p38-dependent elevation of cell surface Fas. In contrast, CCN1 synergized with FasL in H9c2 cells via increasing cytosolic Smac and HtrA2 to counteract anti-apoptotic XIAP. Moreover, we also found that adaptive autophagy was induced in H9c2 cells to restrict the cardiotoxicity of CCN1. In summary, CCN1 plays a detrimental role in cardiac injury by sensitizing cardiomyocytes to FasL-induced apoptosis. CCN1 may represent a new therapeutic target for stressed-induced myocardial injury.
論文目次 中文摘要 I
ABSTRACT III
誌謝 IV
CONTENTS V
FIGURE CONTENTS VIII
1. INTRODUCTION 1
1.1. Cardiomyocyte survival and death 1
1.2. Apoptosis 1
1.3. Autophagy 2
1.4. Crosstalk between apoptosis and autophagy 3
1.5. Microenvironment and cardiomyocytes survival and death 4
1.6. Fas/Fas ligand in cell apoptosis 5
1.7. Fas/Fas ligand in cardiac injury 5
1.8. Extracellular matrix protein CCN family 6
1.9. CCN1 protein and apoptosis 7
1.10 CCN1 and heart 7
2. HYPOTHESIS AND SPECIFIC AIMS 9
3. MATERIALS AND METHODS 10
3.1 Chemicals 10
3.2 Antibodies 12
3.3 Tissue culture supplies 14
3.4 Equipments 14
3.5 Materials provided by other laboratories 15
3.6 Solution formula 15
3.7 Animal 19
3.8 Rat neonatal cardiomyocyte isolation and culture 19
3.9 Cell culture and knockdown 20
3.10 Apoptotic assay 20
3.11 Cell surface expression of Fas 21
3.12 Reactive oxygen species (ROS) measurements 21
3.13 Western blotting and fractionation 21
3.14 Transient transfection with GFP-LC3 21
3.15 Acridine orange staining 21
3.16 Immunofluorescent staining and immunohistochemistry 22
3.17 Mitochondrial outer membrane permeabilization (MOMP) assay 22
3.18 Statistical analysis 22
4. RESULTS 23
4.1 CCN1 and FasL synergize to induce primary cardiomyocyte apoptosis 23
4.2 CCN1 increases Fas expression in primary cardiomyocytes 23
4.3 CCN1 synergizes with FasL to induce H9c2 cardiomyoblast apoptosis 23
4.4 FasL increases XIAP levels in cardiomyoblasts 24
4.5 CCN1 induces Bax translocation and increases cytosolic Smac 25
4.6 Smac and HtrA2 are essential for CCN1/FasL synergism 26
4.7 CCN1 synergizes with FasL through integrin α6β1/HSPG 26
4.8 CCN1-induced intracellular ROS are essential for its synergism with FasL 27
4.9 CCN1-induced MAPK p38 activation is essential for its synergism with FasL 28
4.10 Autophagy and apoptosis are activated in injured myocardium 28
4.11 CCN1 activates autophagy in cardiomyocytes 29
4.12 CCN1 triggers autophagic signaling 30
4.13 Autophagy is activated to repress CCN1-induced apoptosis 30
4.14 CCN1 induces autophagy via integrin α6β1/HSPG and ROS signaling 31
4.15 CCN1 triggers autophagy via modulation of ERK/JNK pathway 32
5. DISCUSSIONS 33
5.1 CCN1 is critical for FasL-induced apoptosis in postmitotic and proliferative cardiomyocytes 33
5.2 CCN1 sensitizes postmitotic cardiomyocytes to FasL-induced apoptosis through ROS/MAPK p38/Fas signaling axis 33
5.3 CCN1 enables FasL-induced apoptosis in cardiomyoblasts by antagonizing XIAP 34
5.4 The sensitivities between of cardiomyoblasts and of primary cardiomyocytes to FasL-induced cardiotoxicity 35
5.5 Adaptive autophagy is activated by CCN1 in cardiomyocytes 36
5.6 Crosstalk between autophagy and apoptosis 36
5.7 ECM protein CCN2 and osteopontin trigger autophagy 37
6. CONCLUSION AND CLINICAL IMPLICATION 39
7. REFERENCES 40
8. FIGURES 49
9. PUBLICATIONS 77
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