臺灣博碩士論文加值系統

水溶性鳥苷酸環化酶(sGC)在血管組織包含內皮細胞及平滑肌細胞當中，扮演了相當重要的角色。sGC的異常導致內皮細胞功能缺損，並產生血管系統相關疾病。反之，sGC的活化則可以促使血管舒張，並且抑制平滑肌細胞的增生與遷移。而在粥狀動脈硬化的病灶處，已有研究顯示sGC在此處的表現以及活性都呈現異常。然而，sGC在巨噬細胞以及粥狀動脈硬化病灶處所扮演的角色和媒介的機制，目前仍尚未明確。因此本篇目的在利用sGC的活化物，[3-(5’-hydroxymethyl-2’furyl)-1-benzyl indazole] (YC-1)探討sGC在巨噬細胞以及粥狀動脈硬化過程當中，是否有參與膽固醇代謝的調控。利用免疫組織染色，我們從小鼠的粥狀動脈硬化病灶中發現了sGC的表現。接著在巨噬細胞中發現，由氧化態低密度脂蛋白所導致的膽固醇累積，在給予了不同濃度的YC- 1之後減輕了這個現象，而這主要是因為YC-1促進了膽固醇的外移。除此之外，YC-1藉由增加ATP結合盒轉運體A1(ABCA1)的蛋白質表現而促進的膽固醇外移，同時不影響到ABCG1，SR-BI，SR-A和CD36的表現。進一步利用阻斷ABCA1功能的抗體，證實了YC-1促進膽固醇外移的確是透過ABCA1。然而ABCA1蛋白表現受YC-1的促進機制仍然不明確，因此我們從轉錄和後轉譯兩個方向來檢視。結果發現YC-1促進ABCA1的表現是透過肝臟X接受器?悛漪﹞炱oABCA1轉錄活性增加，同時不影響ABCA1的蛋白質降解。接著利用載脂蛋白E缺失(apoE-/-)小鼠作為粥狀動脈硬化的病理模式，發現YC-1有效抑制粥狀動脈硬化的病灶大小，並且降低血中的總膽固醇和低密度脂蛋白，同時提升高密度脂蛋白和三酸甘油脂的含量。血清中也發現發炎前物質，包括細胞介白素第六因子、巨噬細胞發炎蛋白二號、腫瘤壞死因子?悕M單核球趨化蛋白一號，在YC-1施打的apoE-/-小鼠中，其分泌都顯著的受到抑制。總結而言，YC-1活化sGC可以在巨噬細胞中透過活化LXR??ABCA1的路徑產生保護效果，並且抑制粥狀動脈硬化的病程發展。

Soluble guanylyl cyclase (sGC) plays pivotal roles in vascular cells including endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). Dysregulation of sGC results in EC dysfunction and the progression of vascular diseases. In contrast, activation of sGC promotes vasorelaxation and the inhibition of proliferation and migration of VSMCs. Moreover, the expression and activity of sGC are altered in atherosclerotic lesions. However, the role and detailed mechanism of sGC in macrophages of atherosclerotic lesions are largely unknown. Therefore, we investigated whether sGC participates in the regulation of cholesterol metabolism in macrophages and atherosclerosis. Immunohistochemistry staining revealed that expression of sGC was restricted in macrophages of mouse atherosclerotic lesions. Treatment with 3-(5’-hydroxymethyl-2’furyl)-1-benzyl indazole (YC-1), a stimulator of sGC, promoted cholesterol efflux and reduced the oxLDL-induced lipid accumulation in macrophage foam cells. Additionally, YC-1 dose-dependently increased protein expression of ATP-binding cassette transporter (ABC) A1, while unaltered the protein expression of ABCG1, scavenger receptor (SR)-BI, SR-A and CD36. In contrast, inhibition of ABCA1 pathway by ABCA1 neutralizing antibody abolished the effects of YC-1 on cholesterol efflux. Moreover, YC-1-induced upregulation of ABCA1 was due to liver X receptor (LXR) ??activated transcriptional activity but not the enhanced protein stability. In vivo studies utilizing apolipoprotein E-null (apoE-/-) mice, an atherosclerotic model demonstrated that administration of YC-1 retarded the development of atherosclerotic lesions accompanied with reduced serum level of total cholesterol and LDL-cholesterol. Serum levels of pro-inflammatory cytokines including interleukin-6, tumor necrosis factor-?? macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 were all attenuated in YC-1-treated apoE-/- mice. In conclusion, activation of sGC by YC-1 leads to LXR??dependent upregulation of ABCA1 in macrophages and may confer the protection from the progression of atherosclerosis.

Table of Contents
? Abbreviation IV
中文摘要 VI
Abstract VIII
Chapter 1 Introduction - 1 -
1.1 Soluble Guanylyl Cyclase (sGC) - 1 -
1.1.1 The Physiological Role of Vascular sGC/ nitric oxide (NO)/ cyclic guanosine 3’, 5’-monophosphate (cGMP) Pathway - 1 -
1.1.2 Alterations of sCG in Vascular Pathology - 3 -
1.1.3 Activation of sGC in Therapeutic Strategy - 5 -
1.2 Atherosclerosis and Macrophage-derived Foam Cells - 9 -
1.2.1 The Pathology of Early-stage Atherosclerosis - 9 -
1.2.2 Macrophage Foam Cells in Early-stage Atherosclerosis - 10 -
1.2.3 The Homeostasis of Cholesterol Metabolism in Macrophages Relies on Scavenger Receptors and Reverse Cholesterol Transporters - 12 -
1.2.4 Scavenger Receptors (SRs)-CD36 and SR-A - 13 -
1.2.5 Reverse Cholesterol Transporters (RCTs)-SR-BI, ABCA1 and ABCG1 - 14 -
1.2.6 Liver X receptor-Retionic X receptor (LXR-RXR) System Regulates Lipid Homeostasis and the Reverse Cholesterol Transport Action - 16 -
1.3 Objective - 19 -
Chapter 2 Materials and Methods - 20 -
2. 1 Reagents and Antibodies - 20 -
2.2 Animals - 20 -
2.3 Immunohistochemical Assessment - 21 -
2.4 Histological Examination - 22 -
2.3 Immunohistochemical Assessment - 23 -
2.5 Cell Culture - 24 -
2.6 Preparation and Modification of Low-density Lipoprotein (LDL) - 24 -
2.7 Oil Red O Staining - 24 -
2.8 Cholesterol Measurement - 25 -
2.9 Dil-oxLDL Binding Assay - 25 -
2.10 Cholesterol Efflux Assay - 26 -
2.11 Reverse Transcription Polymerase Chain Reaction - 26 -
2.12 Quantitative Real-Time Polymerase Chain Reaction - 27 -
2.13 Preparation of Nuclear Extracts - 27 -
2.14 Western Blot Analysis - 28 -
2.15 Transient Transfection and Luciferase Reporter Assay - 29 -
3.16 Statistical Analyses - 29 -
Chapter 3 Results - 30 -
3.1 The Expression of sGC in Atherosclerotic Lesion Areas - 30 -
3.2 The sGC Activator, YC-1 Attenuates Oxidized LDL (OxLDL)-induced Lipid Accumulation in Macrophages - 30 -
3.3 YC-1 Upregulates the Protein Expressions of Reverse Cholesterol Transport-associated Proteins - 31 -
3.4 Activation of sGC Promotes the Transcription of ABCA1 and the Activation of Liver X Receptor ? (LXR?? in Macrophages - 32 -
3.5 YC-1 Attenuates the Development of Atherosclerosis in ApoE-/- Mice - 33 -
Chapter 4 Discussion - 35 -
Chapter 5 Figures - 44 -
Figure 1. The expression of sGC is mainly restricted in the intralesional macrophage foam cells of apoE-/- mice. - 44 -
Figure 2. YC-1 decreases cholesterol accumulation in macrophages. - 45 -
Figure. 3 YC-1 decreases lipid accumulation in macrophages. - 46 -
Figure 4. YC-1 promotes cholesterol efflux in macrophages. - 47 -
Figure 5. YC-1 does not alter the oxLDL binding of macrophages. - 48 -
Figure 6. YC-1 increases the expression of ABCA1 in macrophages. - 49 -
Figure 7. YC-1 does not affect the expression of ABCG1. - 50 -
Figure 8. YC-1 does not affect the expression of scavenger receptor (SR)-BI. - 51 -
Figure 9. YC-1 does not affect the expression of lipid uptake-associated CD36 in macrophages. - 52 -
Figure 10. YC-1 does not affect the expression of lipid uptake-associated SR-A in macrophages. - 53 -
Figure 11. YC-1-stimulated cholesterol efflux is partially abolished by ABCA1 neutralizing Ab. - 54 -
Figure 12. YC-1 promotes the protein expression of ABCA1 in macrophages. - 55 -
Figure 13. YC-1 promotes the gene transcription of ABCA1. - 56 -
Figure 14. YC-1 promotes the gene transcription of ABCA1. - 57 -
Figure 15. YC-1 does not alter the protein stability of ABCA1. - 58 -
Figure 16. YC-1 promotes the presence of LXR? in extracted nuclear protein in macrophages. - 59 -
Figure 17. YC-1 promotes the promoter activity of LXR response element (LXRE) in macrophages. - 60 -
Figure 18. YC-1-elevated promoter activity of ABCA1 is abolished when LXR??interacted sequence on ABCA1 promoter is mutated. - 61 -
Figure 19. YC-1 administration attenuates the development of atherosclerotic lesions in apolipoprotein E-null (apoE-/-) mice. - 62 -
Figure 20. Effect of YC-1 on lipid profile in apoE-/- mice. - 63 -
Figure 21. YC-1 reduces the release of proinflammatory cytokines in apoE-/- mice. - 64 -
Figure 22. Administration of YC-1 leads to the upregulation of ABCA1 and SR-BI in aortic homogenates from apoE-/- mice. - 65 -
References - 66 -

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