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研究生：	吳嘉穎 Wu, Jia-Ying
論文名稱：	探討在肺動脈高壓中YAP/TAZ所扮演的角色以及影響機制 The role of YAP/TAZ in pulmonary arterial hypertension
指導教授：	劉秉彥 Liu, Ping-Yen
學位類別：	碩士 Master
系所名稱：	醫學院 - 臨床醫學研究所 Institute of Clinical Medicine
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	54
中文關鍵詞：	肺動脈高壓、醛固酮、YAP/TAZ 、血管重塑、血管硬化、鹽皮質激素受體拮抗劑
外文關鍵詞：	pulmonary arterial hypertension, aldosterone, YAP/TAZ, vascular remodeling, vascular stiffness, mineralocorticoid receptor antagonists
相關次數：	點閱：71 下載：4
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肺動脈高壓（pulmonary arterial hypertension）是一種慢性且致死率高的疾病，其病徵在於肺動脈重塑導致肺血管阻力升高，而肺動脈高壓的病人若不妥善治療最終會導致右心衰竭。在肺動脈高壓發展時期，血管內的細胞會在持續的壓力環境下，例如發炎作用或者缺氧反應，皆會造成血管細胞的病變以及受損。雖然肺動脈高壓的治療在過去10年中快速發展，例如：從使用非選擇性血管擴張劑到特別針對肺血管擴張，內皮功能和血管重塑的藥物，但由於其複雜的機制和高死亡率，對於治療肺動脈高壓的藥物研究和開發還有進一步的需求。sildenafil是用於治療肺動脈高壓常見藥物之一。然而，在先前的研究指出，在sildenafil長期的臨床研究中，部分肺動脈高壓患者會對該藥物有耐藥性。因此，尋找更有效的藥物來治療肺動脈高壓是至關重要的。而在近期的研究發現血漿中的醛固酮（aldosterone）濃度高低與病人所引起的肺動脈高壓嚴重程度相關。且醛固酮濃度上升會活化氧化壓力訊號路徑（oxidant stress signaling pathways），增加發炎反應，此外還會促進細胞增殖，遷移，細胞外基質重塑和細胞纖維化，並最終導致血管僵硬。
YAP / TAZ 是控制器官生長，細胞增殖和遷移的必需轉錄因子。到目前為止，有許多證據指出YAP/TAZ被鑑定為機械傳導器（mechanotransducers），YAP/TAZ會將接收到的胞外機械力，例如：剪切力（shear stress）、細胞外基質軟硬度，轉換成特定的細胞編程。近年來，一些研究報導 YAP / TAZ 的訊號途徑涉及肺動脈高壓的疾病發展。因此，我們提出 YAP / TAZ 信號傳導和醛固酮在肺動脈高壓疾病中扮演調節細胞重塑以及軟硬度的重要影響因子。
在我們的研究中，我們運用鹽皮質激素受體拮抗劑（mineralocorticoid receptor），也稱為醛固酮拮抗劑來對於野百合鹼（MCT）動物模型進行治療。我們發現在接受MCT注射後而形成肺動脈高壓的的大鼠血清中，醛固酮濃度會升高，且伴隨著在肺動脈中YAP / TAZ蛋白表現量和入核率提高。當MCT大鼠接受鹽皮質激素受體拮抗劑時，可以很明顯觀察到疾病進展得到很大改善，在肺血管的YAP / TAZ蛋白表達量降低，血清中醛固酮水平降低。然而，當MCT大鼠單獨接受sildenafil治療時，卻沒有觀察到這些變化。因此，我們期望鹽皮質激素受體拮抗劑可通過抑制YAP / TAZ活性來改善肺動脈高壓的疾病進展。

Pulmonary arterial hypertension (PAH) is a chronic and lethal disease characterized by progressive remodeling of the distal pulmonary arteries, resulting in elevated pulmonary vascular resistance and, eventually leading to right heart failure. PAH development occurs under sustained and persistent environmental stress, such as inflammation, shear stress and hypoxia. Although the therapy of PAH has evolved rapidly in last 10 years from the use of non-selective vasodilators to drugs that specifically targeting pulmonary vasodilation, endothelial function, and vascular remodeling, there are further needs for the research and development of medicine on PAH due to its complex mechanism and high mortality. Sildenafil, one of the common treatments on PAH, has been proved to benefit on the prognosis of PAH. However, the previous long-term clinical studies about sildenafil indicated that a portion of patients with PAH might have resistance to this drug. Therefore, it’s critical to find out more effective drugs to improve PAH treatment. In recently studies, elevated levels of plasma aldosterone have been documented to correlate with the severity of functional capacity in PAH patients. At a cellular level, hyperaldosteronism activate oxidant stress signaling pathways that decrease levels of bioavailable nitric oxide, increase inflammation. In addition, it promotes cell proliferation, migration, extracellular matrix remodeling, fibrosis, and finally causes vascular stiffness.
Yes-associated protein 1 (YAP) and PDZ-binding motif (TAZ) are known as transcriptional coactivators that are essential for controlling the growth of whole organs, cell proliferation and migration. Until now, many evidences have shown that YAP and TAZ are the conserved mechanotransducers, reading a very diverse set of mechanical cues, from shear stress to extracellular matrix rigidity, and translating them into cell-specific transcriptional programmers. In recent years, several studies reported YAP/TAZ signaling involves in development and progression of PAH. Thus, we proposed that aldosterone through the mineralocorticoid receptor (MR) can modulate pulmonary vascular remodeling and stiffness via activating YAP/TAZ.
In our study, MR antagonists (spironolactone and eplerenone), also known as aldosterone antagonists, were applied on monocrotaline (MCT) animal model. We found that the MCT rats increased serum level of aldosterone and had higher YAP/TAZ protein expression and nuclear translocate ability in the pulmonary arterial structure. While the MCT rats received the MR antagonists were much improved in the disease progression, with decreased YAP/TAZ protein expression and serum level of aldosterone. However, these changes did not observed when the MCT rats got sildenafil alone. Thus, we concluded that MR antagonists could improve PAH progression via repress YAP/TAZ activity.

中文摘要 ................. I 
Abstract ................ III 
誌謝 .................. V 
Contents ................. VI 
Abbreviations ................ X 
Chapter 1. Introduction ............. 1 
1.1 Pulmonary arterial hypertension .......... 1 
1.2 Treatment of pulmonary arterial hypertension ........ 2 
1.3 Hyperaldosteronism and pulmonary arterial hypertension ....... 2 
1.4 Mineralocorticoid receptor antagonists ......... 3 
1.5 Animal model of monocrotaline (MCT) rat ......... 3 
1.6 Mechanobiology .............. 4 
1.7 YAP/TAZ ................ 4 
1.8 Research motivation ............. 5 
1.9 Hypothesis ............... 6 
1.10 Specific aim ............... 6 
Chapter 2. Materials and Methods ........... 7 
2.1 Animal model of PAH ............ 7 
2.1.1 The procedure of MCT-induced-PAH rat models ....... 7 
2.1.2 Treatment protocol ............. 7 
2.2 Histologic sections and staining ............ 8 
2.2.1 Paraffin processing of lung tissue .......... 8 
2.2.2 Haematoxylin and Eosin (H&E) staining32 ......... 8 
2.2.3 Masson’s trichrome staining .......... 8  
2.2.4 Immunofluorescence staining ........... 9 
2.3 Aldosterone extraction ............. 9 
2.4 Cell Culture and Reagents ........... 10 
2.4.1 Cell line ............... 10 
2.4.2 Reagents ............... 10 
2.5 Atomic force microscopy (AFM)25 .......... 10 
2.6 Quantitative real-time polymerase chain reaction (qRT-PCR) ..... 11 
2.7 Western blot assay .............. 11 
2.8 Immunocytochemistry (ICC) ............ 12 
2.9 Ki-67 proliferation assay ............. 13 
2.10 Migration assay .............. 13 
2.11 Statistical analysis .............. 14 
Chapter 3. Results .............. 15 
3.1 Establishment of MCT-induced PAH animal model ........ 15 
3.1.1 The procedure of MCT-induced-PAH rat models ....... 15 
3.1.2 The biological parameter of the MCT-induced-PAH rat models ..... 15 
3.2 Structure and function of pulmonary arterial on rats with MCT treatment ... 15 
3.2.1 The changes of pulmonary image and structure on MCT rat ..... 15 
3.2.2 The changes of ECM protein level on MCT rat ....... 16 
3.3 The serum aldosterone level and YAP/TAZ expression in disease process .... 17 
3.3.1 The changes of serum aldosterone level on MCT rat ....... 17 
3.3.2 YAP/TAZ are highly expressed and nuclear located in MCT-induced PAH .. 17 
3.4 Increased serum level of aldosterone and YAP/TAZ protein expression were critical for vascular cell proliferation in MCT-induced-PAH rats ....... 18 
3.5 The association between aldosterone treatment and YAP/TAZ activity in vitro .. 18 
3.5.1 Short-term aldosterone stimulation induced YAP/TAZ nuclear translocation in SMCs and ECs .............. 18 
3.5.2 Short-term aldosterone stimulation modulated the downstream genes via the activity of YAP/TAZ in SMCs and ECs ......... 19 
3.5.3 Long-term aldosterone treatment changed cell rigidity and increased YAP/TAZ activity in SMCs and ECs ............ 20 
3.6 The cell function in SMCs and ECs by regulation of YAP/TAZ under aldosterone stimulation ................ 21 
3.6.1 Cell proliferation were impaired by YAP-TEAD complex disruptor- Verteporfin (VP) ................ 21 
3.6.2 Migration ability were impaired by VP in SMCs and ECs ..... 21 
Chapter 4. Discussion ............. 23 
4.1 The interaction of different cell type in PAH ......... 23 
4.2 The role of YAP/TAZ involved in PAH.......... 23 
4.3 Divergent functions of YAP and TAZ in the developmental roles and molecular activity
 .................. 24 
4.4 The therapeutic effect and future clinical treatment trends of MR antagonists .. 25 
Chapter 5. Conclusion ............. 27 
References ............... 28 
Figures ................. 33 
Figure 1. Establishment of MCT-induced PAH on rats. ........ 33 
Figure 2. Biological parameters of the experimental rats following the 8-weeks treatments.
 .................. 34 
Figure 3. Representative pulmonary images and immunochemistry staining of the experimental rats following the 8-week treatment. ......... 35 
Figure 4. The expression of collagen Ⅰ, Ⅲ increased under MCT treatment. ... 36 
Figure 5. Aldosterone expression in the serum of MCT-induced PAH animal model. .. 37 
Figure 6. The protein expression of YAP/TAZ in pulmonary vascular. ..... 39 
Figure 7. The proliferate ability increased in MCT-induced rats pulmonary arterial. . 40 
Figure 8. Cell stiffness level of vascular cells under short-term aldosterone stimulation. . 41 
Figure 9. YAP/TAZ nuclear translocate ability of vascular cells under short-term aldosterone stimulation. ............. 43 
Figure 10. Phospho-YAP/TAZ and phospho-LAST1 protein level decreased by treating with different concentrations of aldosterone. .......... 45 
Figure 11. YAP/TAZ protein level were increased via aldosterone stimulation. ... 46 
Figure 12. Downstream target genes of YAP/TAZ were up regulate the expression under aldosterone stimulation. ............. 47 
Figure 13. Cell stiffness assay of vascular cells under short-term aldosterone stimulation. 48 
Figure 14. Long-term aldosterone treatment decreased MST1 protein expression and enhanced YAP/TAZ activity. ............ 50 
Figure 15. Cell proliferation ability of vascular cells were induced through aldosterone stimulation. ............... 51 
Figure 16. Cell proliferation ability of vascular cells were impaired by YAP-TEAD complex disruptor- Verteporfin (VP). .......... 52 
Figure 17. Cell migration ability of vascular cells were impaired by YAP-TEAD complex disruptor- Verteporfin (VP). ............. 54
                                    

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