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系統識別號 U0026-3112201316414200
論文名稱(中文) 內質網壓力傷害參與延腦鼻端腹外側核神經性高血壓角色之研究
論文名稱(英文) The Role of Endoplasmic Reticulum Stress at the Rostral Ventrolateral Medulla in Neurogenic Hypertension
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 1
出版年 102
研究生(中文) 趙詠梅
研究生(英文) Yung-Mei Chao
學號 S58961206
學位類別 博士
語文別 英文
論文頁數 96頁
口試委員 指導教授-賴明德
共同指導教授-華瑜
口試委員-呂增宏
召集委員-許桂森
口試委員-陳慶鏗
中文關鍵字 內質網壓力  延腦鼻端腹外側核  氧化壓力  自噬作用 
英文關鍵字 ER stress  RLVM  oxidative stress  autophagy  PI3K  Akt 
學科別分類
中文摘要 動脈血壓的調控是一複雜的生理現象,除了血管本身調節功能失調外,血液中許多分子或化學物質代謝異常,如:賀爾蒙 (血管收縮素 II)、超氧陰離子、一氧化氮、一氧化碳和中樞神經失調,也會造成高血壓。在中樞神經系統調節血壓恆定的延腦鼻端網狀腹外側核,先前研究已指出,過多的超氧陰離子或過氧化氫會造成延腦鼻端網狀腹外側核過度氧化傷害,進而導致神經性高血壓的形成。內質網壓力與氧化壓力兩者在細胞中常伴隨而生,內質網壓力目前已知在許多腦部神經退化疾病中扮演重要角色,因此我們假設內質網壓力也會促進神經性高血壓的形成,且可能與氧化壓力相互影響,進而影響在延腦鼻端網狀腹外側核調控血壓的功能。本論文實驗目的首先確認高血壓大鼠的延腦鼻端網狀腹外側核表現內質網壓力的現象,接著釐清內質網壓力與氧化壓力在延腦鼻端網狀腹外側核影響血壓調控的因果關係,另一方面希望藉由抑制內質網壓力,保護延腦鼻端網狀腹外側核,使其調控血壓功能穩定,維持血壓處於正常值。實驗設計先建立正常血壓大鼠以周邊或中樞給予血管收縮素 II,造成長期高血壓狀態的動物模式,並用內質網誘發物 (tunicamycin) 誘導產生內質網壓力和增加血壓,並與自發性高血壓大鼠、正常血壓大鼠,比較各動物模式在延腦鼻端網狀腹外側核內質網壓力的差異;在此動物模式下測量活性氧物質 (reactive oxygen species) 的含量,確認氧化壓力傷害的產生,並且進一步測定內質網壓力的訊息傳遞路徑,配合基因抑制 (siGRP78, siLC3B) 或藥物 (tempol, salubrinal) 處理,保護內質網免於傷害,及其抗高血壓之分子機轉。並確定內質網壓力會誘發自體吞噬作用,最後也確定氧化壓力經由活化PI3K/Akt訊息傳遞影響內質網壓力及其調控血壓之相關性。綜合上述系列性研究結果,本論文證明內質網壓力傷害參與延腦鼻端腹外側核神經性高血壓的角色。
英文摘要 Regulation of the arterial blood pressure is a complex and delicate physiological process. Vascular dysfunction, alterations in the humeral factors, including the circulatory metabolites, angiotensin II (Ang II), superoxide anion, nitric oxide and carbon monoxide, are all engaged in pathophysiology of the high blood pressure. At the same time, perturbation of the central cardiovascular regulatory machineries also contributes to pathogenesis of hypertension. It is well established that overexcitation of the premotor neurons in the rostral ventrolateral medulla (RVLM) results in sympathoexcitation and the increase in arterial blood pressure. Previous studies have shown that oxidative stress of an enhanced production of the superoxide anion (O2.-) and/or hydrogen peroxide (H2O2) in the RVLM plays a pivotal role in manifestation of hypertension of the spontaneously hypertensive rats (SHR). The endoplasmic reticulum (ER) is the first compartment of the secretory pathways to rescue unfolded proteins in cells. When misfolded or unfolded proteins accumulate in the ER, the cells activate a self-protective mechanism, termed the ER stress. Prolonged ER stress has been proposed to be involved in the neurodegenerative diseases. In this study, we hypothesized that ER stress may underpin the cellular events leading to the manifestation of redox-associated neurogenic hypertension. We found that in comparison with the normotensive Wistar-Kyoto (WKY) rats, the expression of two major marker proteins of ER stress, glucose-regulated protein 78 (GRP78) and the phosphorylated eukaryotic initiation factor 2α (eIF2α), at RVLM was significantly greater in the SHR. Intraperitoneal or intracerebroventricular infusion of Ang II or direct microinjection of a ER stress inducer, tunicamycin, promoted ER stress and increased the systemic arterial pressure in the normotensive WKY rats. Protection of the RVLM cells from undertaking ER stress by microinjection bilaterally into the RVLM of salubrinal, on the other hand, caused a significant decrease in systolic arterial pressure of SHR, alongside a concomitant suppression of the increased GRP78 expression and downregulation of eIF2α phosphorylation. We further found that ER stress induced activation of autophagy in RVLM, leading to hypertension in the SHR. Finally, we identified that oxidative stress activated the ER stress through the activation of PI3K/Akt signaling and this redox-sensitive activation of PI3K/Akt signaling was engaged in the neurogenic hypertension. Collectively these results suggest that exaggerated ER stress may be an important factor in the manifestation of neurogenic hypertension via redox-sensitive activation of PI3K/Akt pathway and autophagy in the RVLM.
論文目次 Abstract in Chinese ........... i
Abstract ............ ii
Acknowledgement ........... iv
Contents............ v
I. Introduction
I-1 Endoplasmic reticulum stress..........01
I-2 Neurogenic hypertension ...........03
I-3 Rostral ventrolateral medulla..........04
I-4 ER stress and hypertension ...........06
I-5 Reactive oxygen species and oxidative stress .......07
I-6 Superoxide anion and hypertension........09
I-7 Oxidative stress and ER stress.........11
I-8 Autophagy .............12
II. Research aims ..............17
III. Materials and methods
III-1 Animals .............19
III-2 General preparation ..........19
III-3 Measurement of arterial pressure by radiotelemetry.....19
III-4 Power spectrum analysis ...........20
III-5 Microinjection of test agents into the RVLM......21
III-6 Implantation of osmotic minipump........21
III-7 Protein extraction and western blot analysis ......22
III-8 Measurement of ROS (O2
.-) by lucigenin-enhanced chemiluminescence .23
III-9 Small interfering RNA expression vectors.......24
III-10 Phos-tag gels .............24
III-11 Immunohistochemistry..........25
III-12 Double immunofluorescence staining and laser confocal microscoy ..26
III-13 Production and titration of lenti-virus.......26
III-14 High-Performance liquid chromatography.......27
III-15 Cell culture .............27
III-16 Histology .............28
III-17 Statistical analysis............28
IV. Results
IV-1 Augment ER stress in RVLM of SHR........29
IV-2 ER stress in the RVLM precedes the development of hypertension in SHR29
IV-3 Oxidative stress induces ER stress in the RVLM of normotensive WKY
rats...............30
IV-4 Protection from oxidative stress attenuates ER stress in the RVLM of
hypertensive rats………..……………….…………………………..…..30
IV-5 Persistence of ER stress in the RVLM after the peripheral antihypertensive
treatment of SHR...........31
IV-6 ER stress in the RVLM induces pressor responses in normotensive WKY
rats...............31
IV-7 Reduction of ER stress in the RVLM promotes antihypertension..32
IV-8 Autophagy in the RVLM is involved in the hypertension of SHR..33
IV-9 Oxidative stress induces ER stress in the RVLMs of hypertensive rats via
activation of the PI3K/AKT signaling pathway......35
V. Discussion.............37
VI. Conclusions ..............42
VII.References ..............43
Figures ...............56
Appendix ...............93
Figure list ............ vii
Abbreviation............ ix
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