微小核糖核酸在血管內皮細胞與平滑肌細胞中所扮演之角色

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研究生：	陳莉菁 Chen, Li Jing
論文名稱：	微小核糖核酸在血管內皮細胞與平滑肌細胞中所扮演之角色 The role of microRNA in vascular endothelial cells and smooth muscle cells
指導教授：	裘正健 Chiu, Jeng Jiann 陳令儀 Chen, Lin Yi
口試委員:	王寧吳志成林秀芳
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2015
畢業學年度：	103
語文別：	英文
論文頁數：	184
中文關鍵詞：	微小核糖核酸、血管內皮細胞、血管平滑肌細胞、血流剪力、動脈硬化
外文關鍵詞：	microRNA, vascular endothelial cell, vascular smooth muscle cell, shear stress, atherosclerosis
相關次數：	點閱：4 下載：0
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心血管疾病的共同特色是血管壁的慢性發炎反應，而且其併發症常引發病人的高死亡率。雖然目前已了解其致病機轉，但是許多新型分子層面的機制仍然被持續發現。目前已知異常的微小核糖核酸的表現與多種心血管疾病發生具有關連性，而且扮演重要的角色。微小核糖核酸可能藉由調控血管內皮細胞，平滑肌細胞與巨噬細胞的發炎反應與細胞增生等功能而調節心血管疾病的發生。本篇論文主要是探討微小核糖核酸分別在血管內皮細胞與平滑肌細胞所扮演之角色，以及微小核糖核酸調控動脈硬化症與血管再狹窄化所誘發的血管內膜增生之機制。藉由微小核糖核酸晶片分析，微小核糖核酸146a/708，與血管內皮細胞與平滑肌細胞共同培養條件24小時後，會被大量誘發在血管內皮細胞中，而微小核糖核酸451/98則在共同培養6到12小時大量增加，這些表現在血管內皮細胞中的微小核糖核酸會隨著血管內皮細胞與平滑肌細胞共同培養時間的增加而遞減。剪力刺激24小時，微小核糖核酸146a/708/98/451會大量增加。在動物實驗中，這些微小核糖核酸會表現在經由氣球撐開術處理後，呈現正常血流速度的血管內皮層上，而非撐開術處理後，血流阻斷的血管內皮層上。這些微小核糖核酸會藉由負回饋調控機制作用其下游標的基因，進而造成抗發炎功能。此外，重要的剪力轉錄因子NF-E2-related factor-2(Nrf-2)會調控微小核糖核酸146a的大量表現，去除Nrf-2或微小核糖核酸146a則會增進氣球撐開術所誘發的血管內膜增生。大量表現微小核糖核酸146a則會抑制大鼠的氣球撐開術或小鼠的頸動脈結紮術所誘發的血管內膜增生。
微小核糖核酸451會顯著的表現在人類冠狀動脈症血管中的中膜層，在平滑肌細胞體外培養時，纖維狀的膠原蛋白基質會誘發微小核糖核酸451的大量表現，進而抑制平滑肌細胞的增生與發炎反應。相反的，如果加入微小核糖核酸451抑制劑，則會增進平滑肌細胞的增生與發炎反應，進一步分析發現微小核糖核酸451抑制平滑肌細胞的增生與發炎反應的功能是藉由其下游基因Rab5a所調控。在動物實驗中，大量表現微小核糖核酸451或抑制下游基因Rab5a會抑制氣球撐開術所誘發的血管內膜增生。此外，檢測Apolipoprotein E基因缺陷鼠經高膽固醇餵食誘發動脈硬化症或冠狀動脈症病人的血漿，微小核糖核酸451的表現會低於正常組別。利用Apolipoprotein E基因缺陷鼠尾靜脈注射人工合成的微小核糖核酸451後，其經由高膽固醇餵食誘發動脈硬化症的斑塊會顯著的降低。
這些研究結果指出，在血管內皮細胞上的微小核糖核酸146a與平滑肌細胞上的微小核糖核酸451透過其下游基因抑制血管細胞的增生與發炎反應，進而降低血管內膜的增生。此外，微小核糖核酸451有潛力作為檢測冠狀動脈疾病的生物標記，微小核糖核酸146a/451可能作為心血管疾病治療上的應用。

Cardiovascular diseases are commonly appreciated to represent a chronic inflammatory response of the vascular wall, and its complications cause high mortality in patients. Although the pathophysiological mechanisms underlying cardiovascular diseases have been well-established, new molecules that control the progress of these pathologies are continuously discovered. Recently, the aberrant expression of microRNAs (miRNAs) has been revealed in diverse cardiovascular diseases, and recognized as crucial regulators in the progression of these cardiovascular diseases by regulating the function of endothelial cells (ECs), smooth muscle cells (SMCs) and macrophages. Convincingly, miRNAs regulate several cellular processes involved in the development of these cardiovascular diseases, such as vascular inflammation and proliferation. In this thesis, co-culturing ECs with synthetic SMCs under static condition causes initial increases of four anti-inflammatory miRNAs (146a/708/451/98) in ECs followed by decreases below the basal levels at 7 days; the increases for miR-146a/708 peaked at 24 h and those for miR-451/98 lasted for only 6-12 h. Shear stress (12 dynes/cm2) to co-cultured ECs for 24 h augments these four miRNA expressions. In vivo, these four miRNAs are not expressed in neointimal ECs in injured arteries under flow stagnation, but become highly expressed under physiological levels of flow four weeks after balloon injury. MiR-146a, -708, -451, and -98 target interleukin (IL)-1 receptor-associated kinase-1 (IRAK-1), inhibitor of nuclear factor-κB (NF-κB) kinase subunit-, IL-6 receptor, and conserved helix-loop-helix ubiquitous kinase, respectively, to inhibit NF-κB signaling, which exerts negative feedback control on the biogenesis of these miRNAs. NF-E2-related factor-2 (Nrf-2) is critical for shear-induction of miR-146a in co-cultured ECs. Silencing either Nrf-2 or miR-146a in ECs led to increased neointima formation of injured rat carotid artery under physiological levels of flow. Overexpressing miR-146a in ECs inhibits neointima formation of rat or mouse carotid artery induced by injury or blood flow cessation.
Among these miRNAs, the miR-451 was significantly expressed in vascular SMCs of the medial layer in diseased human coronary arteries. In vitro study showed that culturing vascular SMCs on fibrillar collagen increased miR-451 level and suppressed proliferative and anti-inflammatory responses; these effects were diminished by anti-miR-451. Rab5a was inhibited by miR-451 directly targeting to lead to suppression of vascular SMC proliferation and inflammation. In vivo studies on rats indicated that overexpression of miR-451 and lentivirus-mediated Rab5a silencing markedly suppressed the neointima formation induced by balloon injury. The level of circulating miR-451 in blood plasma of patients with coronary artery disease (CAD) and apolipoprotein E knockout mice (ApoE-/-) fed with a high-cholesterol diet was significantly lower than control group. Increase of circulating miR-451 by tail vein injection with agomir-451 in ApoE-/- mice fed with a high-cholesterol diet for three months decreased atherosclerotic lesion formation.
Taken together, these findings indicate that EC miR-146a and SMC miR-451, by respectively targeting IRAK-1 and Rab5a, respectively inhibits inflammation and proliferation in cultured EC and SMCs in vitro, and suppresses neointima formation in injured arteries in vivo. These results suggest the miR-451 may serve as potential biomarker for CAD, miR-146a and miR-451 as a potential target for treatment against neointima formation in cardiovascular diseases.

TABLE OF CONTENTS

Publication List..................................................................................................................IX
Abstract..............................................................................................................................XI
中文摘要..........................................................................................................................XIII
Abbreviation.....................................................................................................................XV
Introduction.....................................................................................................................1
1    Atherosclerosis.............................................................................................................2
1.1    Inflammation.....................................................................................................3
1.2    Fibrous plaques..................................................................................................4
1.3    Advanced lesions and plaque disruption...........................................................4
2 The role of hemodynamic forces in atherogenesis....................................................6
3 The EC dysfunction is an initial step for atherogenesis...........................................8
4 EC-VSMC interaction in response to shear stress.................................................10
5 Regulation of VSMC phenotype and proliferation in atherogenesis..................12
6 The role of miRNAs in cardiovascular diseases......................................................14
6.1 The biogenesis of miRNA..................................................................................14
6.2 The functions of miRNA in ECs response to shear stress..................................18
6.3 The functions of miRNA in VSMC....................................................................19
7 Aims of the study.......................................................................................................22
7.1 MiRNA mediation of endothelial inflammatory response to smooth muscle cells and its inhibition by atheroprotective shear stress................................22
7.2 MiR-451 protects against atherosclerotic plaque formation by directly targeting ras-associated protein 5a in vascular smooth muscle cells............23
Materials and Methods.................................................................................................24
1 Materials.....................................................................................................................25
1.1 Cells....................................................................................................................25
1.2 Reagents.............................................................................................................25
1.3 Antibodies..........................................................................................................26
1.4 Plasmids..............................................................................................................26
2 In vitro study..............................................................................................................27
2.1 EC-sSMC co-culture..........................................................................................27
2.2 Collagen matrices...............................................................................................27
2.3 Transfection........................................................................................................28
2.4 THP-1 Adhesion assay.......................................................................................28
2.5 HASMC proliferation in vitro assay..................................................................29
3 Co-culture flow system..............................................................................................29
4 RNA analysis..............................................................................................................31
4.1 MiRNA array analysis........................................................................................31
4.2 Reverse transcriptase-polymerase chain reaction (RT-PCR) ...........................31
4.3 Quantitative real-time PCR (qPCR) for miRNA and mRNA expressions.........31
4.4 MiRNA stability assay.......................................................................................32
5 MiRNA target gene study.........................................................................................32
5.1 MiRNA target prediction....................................................................................32
5.2 Immunoprecipitation of argonauts 2 (Ago2) complexes....................................32
5.3 3’-UTR luciferase reporter assays......................................................................33
6 Western blot analysis................................................................................................33
7 Cytoplasmic and nuclear protein extraction...........................................................34
8 Analysis of miR-146a promoter binding activity....................................................34
8.1 Electrophoretic mobility shift assay (EMSA) ...................................................34
8.2 Chromatin immunoprecipitation (ChIP) assay...................................................35
8.3 Luciferase reporter assays..................................................................................35
9 Lentiviral specific short hairpin RNA (shRNA) and mature miRNA..................36
10 Animal study............................................................................................................36
10.1 Animal strains...................................................................................................36
10.2 Rat carotid artery balloon injury model...........................................................37
10.3 Ultrasound measurement..................................................................................37
10.4 Secondary arteriotomy and delivery of lentiviral shRNA and miRNAs..........38
10.5 Local oligo delivery and Rab5a gene silence by lentiviral shRNA in vivo.....39
10.6 Mouse vascular injury and lentivirial transfection...........................................39
10.7 ApoE-/- mice in vivo assay...............................................................................40
11 MiRNA in situ hybridization..................................................................................40
12 Immunochemistry...................................................................................................41
13 En face preparation and staining...........................................................................41
14 Quantification of en face atherosclerotic plaque..................................................42
15 Morphometric analysis for neointimal formation................................................43
16 Human study population........................................................................................43
17 Blood plasma collection and circulating RNA extraction....................................44
18 Hemolysis assay.......................................................................................................44
19 Statistical analysis....................................................................................................45
Results............................................................................................................................46
1 MiRNA mediation of endothelial inflammatory response to smooth muscle cells and its inhibition by atheroprotective shear stress..................................................47
1.1 Atheroprotective shear stress augments miR-146a, -708, -451, and -98 expressions in ECs co-cultured with sSMCs......................................................47
1.2 MiR-146a, -708, -451, and -98 directly target IRAK, IKK-γ, IL-6R, and CHUK genes, respectively..............................................................................................48
1.3 MiR-146a, -708, -451, and -98 modulate NF-κB signaling, which exerts negative feedback control on the biogenesis of these miRNAs in co-cultured ECs.....................................................................................................................49
1.4 Nrf-2 is critical for shear-induction of miR-146a in ECs co-cultured with sSMCs.................................................................................................................50
1.5 Shear-inductions of miR-146a, -708, -451, and -98 in ECs co-cultured with sSMCs are regulated by integrins......................................................................51
1.6 MiR-146a, -708, -451, and -98 are not expressed in ECs of neointimal lesions in injured arteries under flow stagnation, but become highly expressed under physiological levels of flow...............................................................................52
1.7 Nrf-2 is involved in shear-induction of EC miR-146a in vivo...........................53
1.8 Administration of Lenti-miR-146a results in reductions in neointimal lesion formation in a mouse carotid artery ligation model............................................53
2 MiR-451 protects against atherosclerotic plaque formation by directly targeting ras-associated protein 5a in vascular smooth muscle cells....................55
2.1 MiR-451 is highly expressed in the medial VSMCs of diseased human coronary arteries in vivo and HASMCs cultured on fibrillar collagen in vitro..................55
2.2 MiR-451 inhibits Rab5a expression by targeting its 3’-UTR............................56
2.3 MiR-451 inhibits HASMC proliferation in vitro via Rab5a..............................56
2.4 MiR-451 inhibits VSMC inflammation in vitro via Rab5a................................57
2.5 MiR-451 reduces vascular neointima formation in vivo....................................57
2.6 Lenti-sh-Rab5a can mediate vascular neointima formation in vivo...................58
2.7 MiR-451 modulates atherosclerotic lesion development in vivo.......................59
Discussion......................................................................................................................61
1 MiRNA mediation of endothelial inflammatory response to smooth muscle cells and its inhibition by atheroprotective shear stress...............................................62
1.1 The anti-inflammatory role of miR-146a, -708, -451, and -98 in co-cultured ECs......................................................................................................................62
1.2 Shear stress induces miR-146a, -708, -451, and -98 expressions in ECs co-cultured with sSMCs......................................................................................63
1.3 Integrin and Nrf-2 are involved in regulation of shear stress-induced these miRNAs in co-cultured ECs................................................................................64
1.4 The effect of miR-146a overexpression on attenuating injury-induced neointima formation.............................................................................................................66
1.5 The clinical perspective of miR-146a.................................................................67
2 MiR-451 protects against atherosclerotic plaque formation by directly targeting ras-associated protein 5a in vascular smooth muscle cells....................69
2.1 The anti-proliferative and inflammatory role of miR-451 in VSMCs...............69
2.2 Rab5a is directly targeted by miR-451 in VSMCs.............................................71
2.3 MiR-451 may serve as a potential biomarker for CAD.....................................72
2.4 The safety of systemic administration of miRNA for therapeutic approach......73
Future Perspective........................................................................................................74
Reference.......................................................................................................................77
Tables and Figures.........................................................................................................92
Appendix.......................................................................................................................167


                                

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