臺灣博碩士論文加值系統

艾黴素(Dox)為一種目前廣泛使用之化療藥物，在臨床上因其造成心臟毒性之特性，使得在使用上受到限制，然而對於艾黴素誘發造成心臟受損之機制仍未清楚。而之前研究結果顯示血管收縮素II受體阻斷劑(Angiotensin receptor blockers, ARBs)具有保護心臟受損之能力，且對艾黴素造成心臟受損亦有保護之功能，但ARBs如何保護Dox所造成之心臟細胞死亡仍未被清楚探究。
先前研究結果顯示第一型血管收縮素II受體(Angiotensin II receptor type I, AT1R) 在Dox造成心臟細胞死亡中扮演重要的角色。因此，本論文主要是研究癌症病人使用化療藥物Dox導致心臟細胞第一型血管收縮素II受體的上調是藉由何種機轉。研究中，我們採用了老鼠心臟衍生的H9c2心臟肌原母細胞，將其給予長時間的Dox，結果顯示AT1R之表現會隨著Dox處理濃度與時間而提高。同時，AT1R表現增加亦會促進心肌細胞凋亡。此外，Dox造成粒線體活性氧化物(mitochondrial ROS) 活化MAPK路徑，進而調控AT1R之基因表現。同時，我們在AT1R的上游promoter區域發現數個熱休克轉錄因子結合片段(heat shock binding elements)。而熱休克轉錄因子2(HSF2)的表現隨著Dox的處理有上升的趨勢。且在先前文獻中指出，熱休克轉錄因子2其與DNA結合活性會經由SUMO化調控。我們也發現Dox處理下熱休克轉錄因子2會進入細胞核。而HSF2過度表現時，亦會提高AT1R表現促進Dox造成心臟細胞死亡。
總結來說，我們發現在動物及細胞實驗中，Dox藉由誘導粒線體ROS釋放進而活化ERK1/2導致HSF2入核轉錄出AT1R造成心臟細胞死亡。

Doxorubicin (Dox), one of the useful chemotherapeutic agents, is limited in clinical use because of its serious cardiotoxicity. However, the mechanism of Dox-induced cardiomyopathy remains unclear. Growing evidences suggest that angiotensin receptor blockers (ARBs) have cardioprotective effects in Dox-induced cardiomyopathy. But the detailed underlying mechanisms of ARBs on the prevention of Dox-induced cardiomyocyte cell death have not been investigated yet.
In our preliminary results showed that angiotensin II receptor type I (AT1R) plays a critical role in Dox-induced cardiomyocyte cell death. We identified those MAPKs signaling pathways, especially ERK1/2 participated in modulating AT1R gene expression by Dox-induced mitochondrial ROS release. Moreover, we found several potential heat shock binding elements (HSE), which can be recognized by HSFs, located at the AT1R promoter region. We observed that HSF2 markedly translocated from cytoplasm to nucleus as foci when cardiomyocytes were damaged by Dox. Furthermore, its DNA binding activity was enhanced by Dox via reducing the sumoylation of HSF2. Overexpression of HSF2 enhanced Dox-induced cardiomyocyte cell death as well. Taken together, we found that Dox-induced mitochondrial ROS release to activate ERKs-mediated HSF2 nuclear translocation and AT1R upregulation for Dox-damaged heart failure in vitro and in vivo.

Acknowledgements I
Contents II
Part I Mitochondrial ROS Generation Induced by Doxorubicin Triggers Erk1/2 Activation and Promotes HSF2-desumoylation and Nuclear Translocation Leading to AT1R Upregulation and Heart Failure 1
Abstract in chinese 2
Abstract 4
Abbreviation 5
1. Introduction
1.1 Doxorubicin 7
1.2 Mechanisms of doxorubicin-induced cardiomyopathy 7
1.3 Renin-angiotensin system (RAS) 8
1.4 Angiotensin II receptor type I (AT1R) 9
1.5 Heat shock transcription factor 10
2. Hypothesis 12
3. Materials and methods
3.1 Animal Investigations 13
3.2 Cell culture and transient transfection 13
3.3 Antibodies and reagents 14
3.4 Immunoblot analysis 14
3.5 Measurement of surface AT1R expression 15
3.6 Co-immunoprecipitation (Co-IP) 15
3.7 RNA extraction and reverse transcription-polymerase chain reaction (RT-PCR) 16
3.8 Nuclear extraction 16
3.9 Luciferase assay 17
3.10 Electrophoretic mobility shift assay (EMSA) 17
3.11 Chromatin immunoprecipitation assay 18
3.12 Immunohistochemistry and immunofluorescence 19
3.13 TUNEL assay 19
3.14 ARB treatment to reduce doxorubicin-induced cardiomyocyte apoptosis 20
3.15 Hematoxylin and Eosin Staining 21
3.16 Echocardiography 21
3.17 Statistical analysis 22
4. Results
4.1 Doxorubicin increased AT1R expression and cardiomyocyte apoptosis by upregulating AT1R mRNA expression via MAPK activation in dose- and time-dependent manner. 23
4.2 Doxorubicin promotes AT1R membrane translocation and Gαq binding ability to the AT1R was related to cardiomyocyte apoptosis 23
4.3 AT1R significantly sensitized to doxorubicin-induced cardiomyocyte cell death 24
4.4 Heat shock transcription factor 2 acted as a transcription factor of AT1R by target to its promoter region 25
4.5 Doxorubicin promotes HSF2 nuclear translocation by suppressing the sumoylation of HSF2 26
4.6 Mitochondria ROS was involved in doxorubicin promoted HSF2 nuclear translocation and AT1R upregulation 27
4.7 Doxorubicin activated AT1R upregulation via ERK1/2 signaling pathways 28
4.8 ERK2 phosphorylation was involved in regulating HSF2 expression 29
4.9 ARB attenuates Doxorubicin cardiotoxicity in rat hearts 29
4.10 ARB attenuated doxorubicin-induced AT1R, activate caspase-3 and PARP expression 30
4.11 ARB protected heart from doxorubicin-induced apoptosis 31
5. Discussion 32
6. References 35
7. Figures 40

Part II P53 Suppressed miR-18 to Activate HSF2 for AT1R Dependent Apoptosis in Dox-induced Cardiotoxicity 54
Abstract in chinese 55
Abstract 57
Abbreviation 59
1. Introduction
1.1 Doxorubicin 61
1.2 Mechanisms of doxorubicin-induced cardiomyopathy 61
1.3 Heat shock transcription factor 62
1.4 MicroRNA-18 62
1.5 p53 63
2. Hypothesis 65
3. Materials and methods
3.1 Animal Investigations 66
3.2 Cell culture and transient transfection 66
3.3 Antibodies and reagents 67
3.4 Cardiac-specific AAV2 vectors generation and recombinant AAV2 virus purification 67
3.5 In vivo gene transfer 68
3.6 miR-18 mimic and antimir transfection 69
3.7 Immunoblot analysis 69
3.8 RNA extraction and miRNA cDNA synthesis 70
3.9 miRNA detection by RT-qPCR 70
3.10 Immunohistochemistry and immunofluorescence 71
3.11 TUNEL assay 71
3.12 Hematoxylin and Eosin Staining 72
3.13 Echocardiography 72
3.14 Statistical analysis 73
4. Results
4.1 MiR-18 participates in the regulation of HSF2 and AT1R expression in cardiomyocytes during doxorubicin treatment. 74
4.2 MiR-18 negatively regulated by p53 in doxorubicin treatment 75
4.3 Cardiac-specific expression of miR-18 by AAV transduction rescued doxorubicin-induced cardiac dysfunction 75
5. Discussion 77
6. References 79
7. Figures 82

PartI
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PartII
1.Raj S, Franco VI, Lipshultz SE: Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment. Current treatment options in cardiovascular medicine 2014, 16:315.
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