博碩士論文 108881601 詳細資訊



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姓名 禾汀(Candra Dwipayana Hamdin)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 雙特異性磷酸酶6在血管平滑肌細胞扮演的角色
(The Role of Dual-specificity Phosphatase 6 in Vascular Smooth Muscle Cells)
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摘要(中) 動脈壁的血管平滑肌細胞 (VSMC) 通常表現出分化的收縮表型； 損傷後，VSMC 去分化為增生和遷移表型，導致內膜增生。 細胞外訊號調節激酶 1/2 (ERK1/2) 參與 VSMC 增生和遷移。 雙特異性磷酸酶 6 (DUSP6) 可以使活化的 ERK1/2 去磷酸化。 我們的目標是研究 DUSP6 是否透過調節 VSMC 增殖和遷移而影響阻塞性血管疾病。 利用小鼠內膜增生模型，我們發現正常未受傷的小鼠動脈的 DUSP6 基線水平較低，而損傷後該水平顯著升高。 與野生型小鼠相比，DUSP6全身性缺陷 (Dusp6–/–) 小鼠的新內膜較小。在體外，IL-1β 誘導 DUSP6 表現並增加 VSMC 增生和遷移，而 缺乏DUSP6會減少IL-1β誘導的VSMC增生和遷移。 有趣的是，DUSP6 的缺乏並不影響 IL-1β 刺激後的 ERK1/2 磷酸化。 ERK1/2 抑制劑 U0126 抑制 IL-1β 誘導 的DUSP6表現。 這些數據顯示在VSMC中，ERK1/2作用在DUSP6上游調節DUSP6的表現量，而不是DUSP6下游之作用物。 IL-1β 降低 VSMC 中細胞週期抑制劑 p27 及與細胞遷移有關的細胞間黏附分子 N-鈣黏蛋白的表現量。有趣的是，即使在IL-1β刺激下缺乏 DUSP6 還是會維持p27 和 N-鈣粘蛋白在較高水平。這些數據揭示了 DUSP6 在調節 VSMC 中 p27 和 N-鈣粘蛋白表現量方面的新功能。 綜上所述，我們的結果顯示，缺乏DUSP6 會透過減少 VSMC 增生和遷移來減低動脈損傷後的新內膜形成，這可能是透過維持高 p27 和 N-鈣黏蛋白水平而導至的。
摘要(英) Vascular smooth muscle cells (VSMCs) of the arterial wall normally exhibit a differentiated, contractile phenotype; upon injury, VSMCs dedifferentiate into a proliferative and migratory phenotype, leading to intimal hyperplasia. The extracellular signal-regulated kinase 1/2 (ERK1/2) participates in VSMC proliferation and migration. Dual-specificity phosphatase 6 (DUSP6) can dephosphorylate activated ERK1/2. Our goal was to investigate whether DUSP6 has a role in occlusive vascular disease by regulating VSMC proliferation and migration. Utilizing a mouse neointimal formation model, we showed that uninjured mouse arteries had low baseline protein level of DUSP6, which was significantly increased after injury. Compared with wild-type mice, DUSP6-deficient (Dusp6–/–) mice had smaller neointima. In vitro, IL-1β induced DUSP6 protein expression and increased VSMC proliferation and migration. Lack of DUSP6 decreased IL-1β-induced VSMC proliferation and migration. Intriguingly, lack of DUSP6 did not affect IL-1β-stimulated ERK1/2 phosphorylation. ERK1/2 inhibitor U0126 prevented DUSP6 induction by IL-1β. These data indicate that in VSMCs, ERK1/2 functions upstream of DUSP6 by regulating DUSP6 protein expression rather than downstream as a substrate of DUSP6. IL-1β decreased protein levels of cell cycle inhibitor p27 and cell-cell adhesion molecule N-cadherin in VSMCs. N-cadherin has been implicated in cellular migration. Interestingly, lack of DUSP6 maintained p27 and N-cadherin at high levels. These data reveal novel functions of DUSP6 in regulating p27 and N-cadherin protein levels in VSMCs. Taken together, our results indicate that lack of DUSP6 attenuated neointima formation following arterial injury by reducing VSMC proliferation and migration, which were likely mediated via maintaining high p27 and N-cadherin protein levels.
關鍵字(中) ★ 雙特異性磷酸酶 6
★ 血管重塑
★ 遷移
★ N-鈣黏蛋白
★ 血管平滑肌細胞
★ 增生
★ 細胞週期素激酶抑制劑		 關鍵字(英) ★ DUSP6
★ vascular remodeling
★ migration
★ N-cadherin
★ VSMC
★ proliferation
★ p27
論文目次 Table of Contents
Declaration ii
Publications iii
中文摘要 v
Abstract vi
Acknowledgments vii
Table of Contents viii
List of Figures xi
List of Table xiii
Abbreviations xiv
Chapter I Introduction 1
1-1 Prevalence of Cardiovascular Diseases 1
1-2 Vascular Physiology and Structure 2
1-2-1 Vascular function 2
1-2-2 Vascular structure 2
1-2-3 Vascular smooth muscle cells (VSMCs) in a healthy vessel 4
1-3 Vascular Pathophysiology: Restenosis 5
1-3-1 Restenosis and percutaneous development 5
1-3-2 Pathophysiology of restenosis 6
1-3-3 Vascular smooth muscle cells (VSMCs) in restenosis 8
1-4 Mitogen-activated protein kinase (MAPK) pathways 11
1-4-1 MAPK and cardiovascular disease 12
1-4-2 ERK1/2 signaling and restenosis 14
1-5 Dual-specificity phosphatase 6 (DUSP6) in cardiovascular diseases 16
1-6 DUSP6 in Metabolic and Inflammatory Related-diseases 21
1-7 Research Background 22
Chapter II Materials and Methods 25
2-1 Animal Care and Genotyping 25
2-2 Neointimal Hyperplasia Model Procedure 26
2-3 Histomorphometric Analysis and In Vivo Proliferation Assay 26
2-4 Isolation and Culture of Primary VSMCs 27
2-5 ERK1/2 Inhibition 27
2-6 Dusp6 Overexpression and Knockdown 28
2-7 BrdU Proliferation Assay 28
2-8 Protein Analysis and Western Blotting 29
2-9 Wound Healing Assay 29
2-10 Phalloidin Staining 30
2-11 Statistical Analysis 31
Chapter III Results 32
3-1 Arterial Injury Leads to Neointimal Formation and Induces DUSP6 in Mice 32
3-2 Inflammatory Cytokine IL-1β Induces DUSP6 Protein Expression and VSMC Proliferation 33
3-3 DUSP6 Knockdown Attenuates VSMC Proliferation 34
3-4 Deletion of Dusp6 in Mice Mitigates Intimal Hyperplasia after Arterial Injury and Inhibits VSMC Proliferation In Vitro 35
3-5 Deletion of Dusp6 in Mice Reduces BrdU-positive Cells After Arterial Denudation 36
3-6 ERK1/2 Activation Precedes Induction of DUSP6 Protein Expression by IL-1β in VSMCs 36
3-7 Inhibition of ERK1/2 Diminishes DUSP6 Protein Expression and Attenuates VSMC Proliferation 37
3-8 Lack of DUSP6 in VSMCs Increases Cell Cycle Inhibitors of Both Total p27 and Phospho-p27 38
3-9 DUSP6 Deficiency in VSMCs Reduces Cellular Migration Capacity 39
3-10 DUSP6 deletion in VSMCs does not affect Cellular Spreading and Focal Adhesion Assembly-Disassembly instead Reduces Lamellipodia Protrusion 40
3-11 Lack of DUSP6 in VSMCs Augments Basal Protein Levels and Sustains Elevated Levels of N-Cadherin 41
Chapter IV Discussions 43
4-1 General Discussion 43
4-2 Study Limitation 48
Chapter V Conclusions 50
Bibliography 51
Figures 56
Appendix A. List of Antibodies 78
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指導教授 林秀芳 陳盛良(Shaw-Fang Yet Shen-Liang Chen) 審核日期 2024-1-12
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