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研究生： 張瑋婷
Chang, Wei-Ting
論文名稱： 透過微型核糖核酸-21/ pitx2c路徑探討二尖瓣膜逆流誘發心臟再塑形及心房顫動之機轉
Mitral regurgitation induced shear stress exacerbated cardiac remodeling and atrial fibrillation associated with miR-21/pitx2c pathway
指導教授： 劉秉彥
Liu, Ping-Yen
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2023
畢業學年度： 111
語文別： 英文
論文頁數： 74
中文關鍵詞： 二尖瓣逆流 、微型核糖核酸-21 、心房顫動 、細胞凋亡 、鈣離子恆定
外文關鍵詞： mitral regurgitation, miR-21, atrial fibrillation, apoptosis, calcium homeostasis
ORCID： https://orcid.org/0000-0001-9525-2144
ResearchGate： https://www.researchgate.net/profile/Wei_Ting_Chang6
相關次數： 點閱：131  下載：7 
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    • 退化性二尖瓣逆流(mitral regurgitation; MR)是常見的心臟疾病，因瓣膜的缺損而造成血液從左心室逆流回左心房，造成液體過負荷(volume overload) 最終引發心肌纖維化，心臟功能異常以及心律不整。目前雖有侵入性瓣膜置換手術，但仍缺乏有效的藥物治療。過去MR模式主要建立在大動物上，花費及死亡率皆高，藉超音波導引我們成功建立微創MR老鼠模型，是探討MR致病機轉一大利器。過往研究指出微型核糖核酸(miRNA)在各種心臟疾病扮演重要角色，但其於二尖瓣逆流造成之擾流對於心肌細胞的調控機制仍待釐清。本研究透過臨床病患心房組織，新穎的小動物和剪力細胞模型，探討微型核糖核酸-21 (miR-21)在二尖瓣逆流患者之調控。利用次世代定序，我們發現 miR-21在二尖瓣逆流患者的血清和心房細胞呈現高度表現。值得注意的是— miR-21在出現心房顫動(AF)的二尖瓣逆流患者呈現顯著上升，並且和調控離子通道的pitx2c表現下降相關。透過細胞模型模擬二尖瓣逆流時的微環境，我們發現剪力會誘使心房細胞凋亡和產生細胞質鈣離子的過度負荷。而抑制心房細胞的miR-21表現則可改善細胞凋亡，間隙連接和鈣離子恆定。藉由報導基因，我們也證實miR-21可以直接調控pitx2c。透過二尖瓣逆流小鼠模型，我們也發現二尖瓣逆流造成的心房纖維化，血流動力失能和心房顫動在miR-21基因剔除鼠獲得顯著改善。進一步在臨床應用層面，我們測試兩種美國食品藥物管理局核准之心衰竭藥物—血管收縮素受體腦啡肽酶抑制劑(ARNI)以及鈉-葡萄糖協同轉運蛋白2抑制劑(SGLT2 inhibitor), 發現兩者皆可在小動物模型上，降低miR-21於血液及心房組織的表現，且能改善二尖瓣逆流造成的心肌功能異常和纖維化。而回歸臨床，我們在二尖瓣逆流的老鼠模型上，測試兩種臨床上用於治療心衰竭的新穎藥物ARNI以及SGLT2i並發現兩者皆可減少血清及心肌的miR-21表現，並改善心臟功能。我們的研究成果指出-- miR-21/ pitx2c路徑在血流剪力造成之心臟再塑型和心房顫動扮演重要角，未來更期望能發展出二尖瓣逆流與心臟衰竭疾病新穎診斷與治療策略。

    Degenerative mitral regurgitation (MR), caused by the disruption of the mitral valve, induces not only the residual blood within the heart (volume overload) but triggers shear stress related cardiac fibrosis, dysfunction and arrhythmogenesis. Although valvular replacement surgeries may cease the progression of MR, it lacks pharmacological options for patients who cannot tolerate invasive procedures. Previous studies focused on large animal model of MR but the cost and mortality were high. Using an echo guided, minimal invasive technique, we established a rodent model of MR, which is useful in studying the mechanism of MR. MicroRNAs could regulate cardiac fibrosis and hypertrophy under mechanical stresses but their roles in degenerative MR remain uncertain. Hereby, through a multidiscipline approach including clinical tissues, novel animal and in vitro shear stress models, we investigated the impact of miR-21 in patients with MR. Using next generation sequencing and qPCR, miR-21 was observed with a high expression in the cardiomyocytes and sera in patients with MR. Notably, the high expression of miR-21 was most significant in MR patients with atrial fibrillation (AF) and was associated with a down-regulation of paired-like homeodomain transcription factor 2C (pitx2c), a pivotal gene regulates ion transport and influences AF. Through a microflow system mimicking the microenvironment of MR, we found that the shear stress triggered up-regulation of apoptosis and calcium overload associated markers in atrial cardiomyocytes. Suppressing miR-21 by a miR-21 inhibitor reduced apoptosis and maintained the function of gap junction as well as calcium homeostasis. Mechanistically, the reporter assay supported that miR-21 directly regulated the expression of pitx2c. In the mouse model of MR, abolishing miR-21 rescued MR induced myocardial fibrosis, hemodynamic dysfunction and provoked AF. For the potential applications of clinical uses, we tested the effects of two FDA-approved heart failure drugs, angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter-2 (SGLT2) inhibitor, in the rat model of MR. Notably, both drugs suppressed the circulating and cardiac expressions of miR-21 and mitigated MR induced myocardial dysfunction and fibrosis. Collectively, our findings highlighted the regulatory mechanism of miR-21/pitx2c pathway in shear stress triggered cardiac remodeling and AF in patients with degenerative MR.

    Abstract I Chinese abstract II Acknowledgement III Contents IV Figure list VI Abbreviations VIII Chapter 1. Introduction 1 1.1 The cardiac remodeling in patients with mitral regurgitation (MR) 1.2 The effect of shear stress on the heart 1.3 The role of miRNA in cardiac hypertrophy and heart failure 1.4 The cardiac remodeling of the left atrium and atrial fibrillation in MR 1.5 The involvement of microRNAs in the development of atrial fibrillation 1.6 Regulatory effects of shear stress on miRNAs expression in cardiac cells 1.7 Calcium homeostasis in shear stress and cardiac diseases 1.8 The PITX2C in MR-induced cardiac remodeling Chapter 2. Objective and Specific Aims 13 Chapter 3. Materials and Methods 14 3.1 Clinical study design and human left atrial tissue collections 3.2 Next generation sequencing analysis of left atrial tissues 3.3 MicroRNA expression and quantitative real time-polymerase chain reaction 3.4 Animal models of degenerative MR and animal study designs 3.5 Animal echocardiography 3.6 Measurements of electrocardiography in animals 3.7 Pressure-volume loop 3.8 Programmed atrial burst pacing for atrial fibrillation provocations 3.9 Histology analysis 3.10 Cell cultures 3.11 Microflow mediated shear stress system 3.12 In situ hybridization with miR-21 probe 3.13 Ca2+ measurement 3.14 Luciferase vector construction 3.15 Western blotting 3.16 Statistical analysis Chapter 4. Results 22 4.1 A high expression of miR-21 in left atrial cardiomyocytes was associated with apoptosis and arrhythmogenesis in patients with mitral regurgittaion 4.2 A negative correaltion of miR-21 with pitx2c/tbx5 expressions in left atrial cariomyocytes in patients and rat model with MR 4.3 The high cardiac expression of miR-21 was associated with an up-regulations of apoptosis, atrial fibrillation and cardiac fibrosis in the rodent model of MR 4.4 Suppressing miR-21 mitigates shear stress-induced apoptosis and calcium disturbance in HL-1 cardiomyocyte 4.5 MR triggered myocardial dysfunction were rescued in miR-21-/- mice 4.6 Abolishing miR-21 mitigated MR induced hemodynamic compromise and atrial fibrillation susceptibility 4.7 Abolishing miR-21 improved MR induced cardiac fibrosis, apoptosis and intra-cellular calcium overload 4.8 FDA-approved drugs for heart failure improves MR induced cardiac dysfunction and arrhythmogenesis, which is associated with miR-21 expression 4.9 The effect of ARNI on electrophysiology, arrhythmogenesis and functional capacity in the rodent model of MR Chapter 5. Discussion 30 5.1 Mini-invasive rodent model of MR 5.2 Molecular mechanisms of MR induced cardiac remodeling 5.3 The effect of novel HF drugs on degenerative MR 5.6.1 ARNI for the Treatment of MR 5.6.2 DAPA for the treatment of MR 5.4 MR induced arrhythmogenesis and calcium signal disturbance 5.5 Shear stress induced calcium homeostasis 5.6 Study limitations 5.7 Future perspectives Chapter 6. Conclusion 36 References 37 Figures 48

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