臺灣博碩士論文加值系統

在中樞神經系統損傷情形下，常伴隨著星狀細胞形態及基因表現的改變。研究顯示中樞神經系統致病機轉中，過度的 MMP-9活性及NO產量已被證實與血腦障壁通透性增加、白血球浸潤及持續性發炎反應有關。腦部創傷或缺血性損傷導致血腦障壁瓦解，並提高中樞神經露暴於與神經退化性疾病相關的危險因子– oxLDL的機率。另一方面，組織缺氧或缺血性損傷也會誘發中樞神經系統釋放ET-1，並作用於其G蛋白偶合受體。然而oxLDL與ET-1調控MMP-9及iNOS在星狀細胞表現的詳細機轉目前仍未明。因此，本論文主要探討在星狀細胞中oxLDL與ET-1刺激MMP-9及iNOS表現的分子機轉，及其後續引發細胞功能上的改變。由實驗結果顯示，oxLD與ET-1藉由增加MMP-9及iNOS表現量而調節星狀細胞的活化反應，進而影響腦部損傷後神經發炎情形。
本篇論文第一部份主要探討oxLDL誘發MMP-9表現及其訊息傳遞機轉。實驗結果證實在鼠腦星狀細胞中，oxLDL透過MAPK活化轉錄因子AP-1進而調控MMP-9的表現。Gelatin zymography、RT-PCR及Western blotting等分析結果顯示，Akt、JNK1/2及p42/p44 MAPK的磷酸化均參與在oxLDL誘發MMP-9 表現的調控機轉。此外為了驗證AP-1在oxLDL誘發MMP-9基因表現中所扮演的角色，我們進一步以ChIP assay證實在活體中的確可觀察到oxLDL促使 c-Fos及c-Jun 結合至MMP-9 promoter；另一方面，將 MMP-9 promoter中AP-1 binding site進行突變後，所產生的AP-1 binding site-mutated MMP-9 promoter construct則無法受oxLDL活化。綜合以上實驗結果可得知，在鼠腦星狀細胞中，oxLDL經由PI3-K/Akt、JNK1/2及p42/p44 MAPK造成AP-1活化，進而促使 MMP-9基因的表現。
本篇論文第二部份主要探討 PKC-及p42/p44 MAPK/Elk-1在oxLDL誘發 MMP-9表現中扮演的角色。由實驗結果得知，在星狀細胞中oxLDL經由 PKC-/p42/p44 MAPK引發轉錄因子Elk-1活化而促進MMP-9的表現。分別以 ChIP assay證實在活體中Elk-1、p300 HAT及acetylated histone-4結合至MMP-9 promoter的反應呈現時間依存性的增加；並將MMP-9 promoter中Elk-1 binding site進行突變所產生的Elk-1 binding site-mutated MMP-9 promoter construct轉殖入細胞，發現oxLDL無法啟動MMP-9 luciferase活性。利用migration assay更證實在星狀細胞中，由PKC-/p42/p44 MAPK/Elk-1路徑所導致的proMMP-9表現對於 oxLDL 引起的細胞遷移性有直接且顯著的貢獻。
接下來我們更深入探討Elk-1、NF-B及AP-1是否參與在由ET-1所誘發 MMP-9表現的分子機轉中。實驗結果顯示，ET-1透過其 ETB 接受器活化 MMP-9基因轉錄作用。當ET-1結合至其偶合Gi/o及Gq蛋白之ETB接受器時，經由 p42/p44 MAPK進而促使包括Elk-1，NF-B及AP-1 (c-Jun/c-Fos)等轉錄因子的活化。這些受活化的轉錄因子轉位至細胞核，並結合至其位於MMP-9 promoter中相對應的結合序列並啟動MMP-9基因表現。功能性試驗也發現ET-1正向調控 MMP-9表現量能加強星狀細胞的遷移性。由以上實驗結果可得知，在星狀細胞中，藉由ETB接受器引發Elk-1、NF-B及AP-1等轉錄因子的活化對於ET-1誘發 MMP-9基因表現是重要且必須的調控因子。
此外，我們也將焦點放ET-1如何調控iNOS表現、NO產生及促進MMP-9活化的訊息傳遞路徑。實驗結果證明當星狀細胞受到ET-1作用下，會透過ETB 接受器誘發iNOS表現及NO產生。我們觀察到ET-1能引起由c-Src所傳遞之 PI3K/Akt、p42/p44 MAPK及NF-B活化，開啟iNOS基因轉錄；隨之產生的NO則能造成MMP-9之tyrosine nitration修飾作用，進而加強星狀細胞之遷移性。上述實驗結果說明在星狀細胞中，由 ETB、c-Src、PI3K/Akt 及p42/p44 MAPK調節之NF-B活性在ET-1誘發iNOS基因表現中扮演重要的角色。
以上實驗結果有助於闡述 oxLDL 及ET-1作用在星狀細胞所引發訊號分子及細胞核內的co-activators所參與調控細胞生理反應之分子機轉模式。總結而言，我們證實了在中樞神經系統疾病的發展過程中，oxLDL及ET-1藉由提升 MMP-9 表現與NO產量進而促進星狀細胞的遷移性。了解oxLDL及ET-1/ETB 系統調控 MMP-9及iNOS表現之分子機轉及其後續引發星狀細胞功能性的改變，對於與MMP-9、NO及iNOS表現量相關的腦部疾病能提供合理的治療應用性。

Emerging evidence suggests that astrocytes undergo large morphologic and gene expression changes in response to central nervous system (CNS) injury. In the CNS pathology, uncontrolled metalloproteinase-9 (MMP-9) activity and nitric oxide (NO) production are implicated in the increase of blood–brain barrier (BBB) permeability, the entry of leukocytes into the CNS, and sustained inflammatory responses. After traumatic and ischemic brain insults, disruption of the BBB raises the possibility of exposing the CNS to oxidized low-density lipoprotein (oxLDL), a risk factor implicated in neurodegenerative diseases. Hypoxic/ischemic injury also elicits endothelin-1 (ET-1) release in the CNS, behaving through G-protein coupled ET receptors. However, the detailed mechanisms of oxLDL and ET-1 action related to MMP-9 and iNOS expression and NO release on rat brain astrocytes remain largely unknown. Thus, this thesis focuses on investigating the signaling pathways by which oxLDL and ET-1 induced MMP-9 and iNOS expression and the functional consequences in astrocytes. Our results concluded that up-regulation of MMP-9 and iNOS induced by oxLDL and ET-1 may contribute to reactive responses of astrocytes after brain insults.
First, the mechanisms underlying oxLDL-induced MMP-9 expression were investigated. We found that oxLDL induces expression of proMMP-9 via a mitogen-activated protein kinase (MAPK)-dependent activator protein-1 (AP-1) activation in rat brain astrocyte (RBA)-1 cells. Results revealed by gelatin zymography, RT-PCR, and Western blotting analyses showed that oxLDL-induced proMMP-9 gene expression was mediated through Akt, c-Jun N-terminal kinase (JNK1/2), and p42/p44 MAPK phosphorylation in RBA-1 cells. Moreover, the regulation of MMP-9 gene transcription by AP-1 was confirmed by chromatin immunoprecipitation (ChIP) assay which indentified the in vivo binding of c-Fos and c-Jun to the MMP-9 promoter, and by MMP-9 luciferase activity which was totally lost in cells transfected with the AP-1 binding site-mutated MMP-9 promoter construct (mt-AP1-MMP-9). These results suggest that oxLDL-induced proMMP-9 expression is mediated through phosphoinositide 3-kinase (PI3-K)/Akt, JNK1/2, and p42/p44 MAPK leading to AP-1 activation.
Next, the roles of protein kinase C- (PKC-) and p42/p44 MAPK/Elk-1 cascades in oxLDL-induced MMP-9 expression were investigated. OxLDL induced MMP-9 expression via a PKC-/p42/p44 MAPK-dependent Elk-1 activation in RBA-1 cells. In vivo binding of Elk-1 to the MMP-9 promoter was evaluated by ChIP assay, revealing that oxLDL stimulated a time-dependent increase in binding of Elk-1 and p300 histone acetyltransferase (HAT), and sequential acetylated histone-4 to the MMP-9 promoter. Elk-1-mediated MMP-9 gene transcription was confirmed by transfection with an Elk-1 binding site-mutated MMP-9 promoter construct (mt-Ets-MMP9), which blocked oxLDL-stimulated MMP-9 luciferase activity. For astrocytic migration, the results suggested that the PKC-/p42/p44 MAPK/Elk-1-dependent proMMP-9 up-regulation is essential for the initiation of cell migration by oxLDL in RBA-1 cells.
Furthermore, the participation of Elk-1, nuclear factor-κB (NF-B), and AP-1 in ET-1-induced proMMP-9 expression was proved. The data showed that ET-1-induced proMMP-9 expression was mediated through an ETB-dependent transcriptional activation. Engagement of Gi/o- and Gq-coupled ETB receptor by ET-1 led to activation of p42/p44 MAPK and then activated transcription factors including Elk-1, NF-B, and AP-1 (c-Jun/c-Fos). These activated transcription factors translocated into nucleus and bound to their corresponding binding sites in MMP-9 promoter, thereby turning on MMP-9 gene transcription. Functionally, up-regulation of proMMP-9 by ET-1 enhanced the migration of astrocytes. Taken together, these results suggested that in astrocytes, activation of Elk-1, NF-B, and AP-1 by ETB-dependent p42/p44 MAPK signaling is necessary for ET-1-induced MMP-9 gene up-regulation.
Moreover, we demonstrated that exposure of astrocytes to ET-1 results in the iNOS up-regulation, NO production, and MMP-9 activation in astrocytes. Our data showed that ET-1-induced iNOS expression and NO production were mediated through an ETB-dependent transcriptional activation. ET-1 exerted the activation of c-Src-dependent PI3K/Akt and p42/p44 MAPK and NF-B, thereby promoting iNOS gene transcription. Sequential NO production enhanced astrocytic migration through the tyrosine nitration of MMP-9. These results suggested that in astrocytes, activation of NF-B by ETB-dependent c-Src, PI3K/Akt, and p42/p44 MAPK signalings is necessary for ET-1-induced iNOS gene up-regulation.
Inclusion, we provide the mechanisms of oxLDL and ET-1 action on astrocytes, supporting the hypothesis that oxLDL and ET-1 contribute to the migration of astrocytes and the increased NO level involved in expression of MMP-9 leading to the development of CNS diseases. Understanding the mechanisms of MMP-9 and iNOS expression and functional changes regulated by oxLDL and ET-1/ETB system on astrocytes may provide rational therapeutic interventions for brain injury associated with the increased levels of MMP-9, iNOS, and NO.

指導教授推薦書
論文口試委員會審定書
論文著作授權書............................................iii
Acknowledgements (誌謝)..................................iv
Abbreviations (縮寫表)....................................v
Pharmacological Inhibitors (藥理性抑制劑).................vii
Abstract in Chinese (中文摘要)..........................viii
Abstract in English (英文摘要)............................xi
Table of Contents (目錄)................................xiv

CHAPTER I. Introduction
SECTION 1. Background and significance...................2
SECTION 2. Specific aims................................19
SECTION 3. Appended figures and tables..................20

CHAPTER II. Materials and Methods
SECTION 1. Materials....................................33
SECTION 2. Methods......................................34

CHAPTER III. Oxidized Low-density Lipoprotein Induces Matrix Metalloproteinase-9 Expression via a p42/p44 MAPK- and JNK-dependent AP-1 Pathway in Brain Astrocytes
SECTION 1. Introduction.................................43
SECTION 2. Results......................................46
SECTION 3. Discussion...................................52
SECTION 4. Figures and legends..........................55

CHAPTER IV. Oxidized Low-Density Lipoprotein Induces Matrix Metalloproteinase-9 Expression via PKC-/p42/p44 MAPK/Elk-1 Cascade in Brain Astrocytes
SECTION 1. Introduction.................................75
SECTION 2. Results......................................77
SECTION 3. Discussion...................................83
SECTION 4. Figures and legends..........................85

CHAPTER V. Endothelin-1 Enhances Cell Migration via Matrix Metalloproteinase-9 Up-regulation in Brain Astrocytes
SECTION 1. Introduction................................102
SECTION 2. Results.....................................104
SECTION 3. Discussion..................................110
SECTION 4. Figures and legends.........................114

CHAPTER VI. Nitric Oxide Production Stimulated by Endothelin-1 Enhances Astrocytic Migration via the Tyrosine Nitration of Matrix Metalloproteinase-9
SECTION 1. Introduction................................132
SECTION 2. Results.....................................134
SECTION 3. Discussion..................................138
SECTION 4. Figures and legends.........................142

CHAPTER VII. Potential Signaling Pathways Contribute to Endothelin-1-Induced Matrix Metalloproteinase-9 and Inducible Nitric Oxide Synthase Expression in Brain Astrocytes
SECTION 1. Results.....................................161
SECTION 2. Figures and legends.........................163

CHAPTER VIII. Conclusion and Perspectives
SECTION 1. Conclusion and perspectives.................176
SECTION 2. Summary.....................................178

PUBLICATIONS...........................................180
REFERENCES.............................................181

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