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博碩士論文 etd-0728106-193045 詳細資訊
Title page for etd-0728106-193045
論文名稱
Title
Neuropeptide Y 在大鼠中樞心臟血管調控之分子機制探討
Investigation of the Molecular Signaling Mechanisms of Neuropeptide Y in Central Cardiovascular Control of Rats
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
131
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2006-06-16
繳交日期
Date of Submission
2006-07-28
關鍵字
Keywords
一氧化氮、心臟血管、血壓
Cardiovascular, NO, BP
統計
Statistics
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中文摘要
神經胜肽Y (Neuropeptide Y)是一個具有36個胺基酸的多胜肽,它存在於中樞及周邊神經系統中,會與Gi/Go蛋白偶合性受體結合去進行其生物功能。過去已經被證實過,在大鼠的孤立束核中神經胜肽Y具有降血壓的潛力,而且在中國倉鼠卵巢細胞也證實活化的神經胜肽Y Y1受體與Y2受體都會產生ERK磷酸化作用。一氧化氮存在於中樞調控心血管有關的區域,例如孤立束核及頭腹側腦幹區。最近之研究報告指出,若抑制此區域內一氧化氮的產生可引起持續性高血壓及抑制感壓反射之活性。我們之前的研究顯示在此區域內所產生之一氧化氮對中樞心臟血管系統之調控扮演極重要之角色。過去也證實,神經胜肽Y會促使人類皮下動脈擴張是透過一氧化氮依賴性途徑。本研究更進一步探討神經胜肽Y在孤立束核中心臟血管調控之分子機制。單側微量注射神經胜肽Y到WKY大鼠的孤立束核中,產生明顯的血壓下降及心博舒緩現象。前處理選擇性非胜肽神經胜肽Y Y1受體之拮抗劑BIBP 3226,Gi/Go蛋白之抑制劑Pertussis toxin和MEK抑制劑PD98059明顯的抑制神經胜肽Y所引起的心血管作用。西方墨點分析以及免疫組織染色結果顯示神經胜肽Y及神經胜肽Y Y1作用劑[Leu31 Pro34]神經胜肽Y會增加ERK磷酸化作用,且BIBP 3226及PD 98059會明顯抑制ERK之磷酸化。非選擇性一氧化氮合成酶抑制劑L-NAME和內皮性一氧化氮合成酶選擇性抑制劑L-NIO明顯的抑制神經胜肽Y所引起的心血管作用。但是神經性一氧化氮合成酶選擇性抑制劑7-NI及神經性一氧化氮合成酶專一性抑制劑Vinyl-L-NIO並不會引起任何變化。西方墨點分析以及免疫組織染色結果顯示NPY會引起內皮性一氧化氮合成酶磷酸化作用,但是神經性一氧化氮合成酶則沒有此現象。我們的結果顯示神經胜肽Y是透過神經胜肽Y Y1受體所引起ERK1/2磷酸化作用,且神經胜肽Y所引起的心血管作用是透過內皮性一氧化氮合成酶-一氧化氮傳遞路徑。
Abstract
Neuropeptide Y (NPY) is a 36-amino-acid polypeptide that exerts its biological action through Gi/Go-protein coupled receptors in the central and peripheral nervous systems. It has been demonstrated to have potent depressor effect in the nucleus tractus solitarii (NTS) of rats, and activation of both NPY Y1 and Y2 receptors would phosphorylate ERK in CHO K1 cell. Brain stem nuclei such as nucleus of tractus solitari (NTS) and rostral ventrolateral medulla (RVLM) are innervated by neurons capable of synthesizing nitric oxide (NO), and inhibition of NO synthesis in these areas cause sustained hypertension and decrease baroreceptor sensitivity. Our previous studies already suggested that NO produced in the braistem nuclei play an important role in cardiovascular regulation. It was shown that NPY induces vasodilation of human subcutaneous arteries by a NO dependent pathway. In the present study, we investigated the molecular signaling mechanisms involved in NPY-induced cardiovascular modulation in NTS. Unilateral microinjection of NPY into the NTS of WKY rats produced prominent depressor and bradycardic effects. Pretreatment with a selective non-peptide neuropeptide Y1 (NPY1) receptor antagonist BIBP3226; Gi/Go-protein inhibitor Pertussis toxin, MEK inhibitor PD98059, significant attenuated the cardiovascular response evoked by NPY. Western blot and immunohistochemistry studies showed NPY and NPY Y1 agonist [Leu31 Pro34] NPY increased ERK1/2 phosphorylation, and PD98059, BIBP3226 attenuated the NPY-induced phosphorylation significantly. Non-selcetive NOS inhibitor L-NAME and eNOS preferential inhibitor L-NIO significantly attenuated the cardiovascular response evoked by NPY, however nNOS preferential inhibitor 7-NI and nNOS specific inhibitor Vinyl-L-NIO did not cause any changes. Western blot and immunohistochemistry studies showed NPY increased eNOS phosphorylation, but not nNOS. Our results showed that NPY induced ERK1/2 phosphorylation through NPY Y1 receptor, and its downstream eNOS-NO pathway involved in NPY mediated cardiovascular effects.
目次 Table of Contents
1.Introduction……………………………………...…………………………...1

1.1 Cardiovascular regulation by brainstem nuclei……………………………….…..……1
1.2 Neuropeptide Y…………………………………………………………………….…..3
1.3 Neuropeptide Y receptor subtypes…………………………………………….….……5
1.4 Nitric Oxide Signaling in Central Cardiovascular Regulation…………………….…..7
1.5 Mitogen-Activated Protein Kinases (MAPK)…………………………………………9
1.6 Regulation of nitric oxide production involved AKT………………………………...10
1.7 Regulation of nitric oxide production involved MAPK…………………………....…11
1.8 p90 ribosomal S6 kinases (RSKs)…………………………………………….………12
1.9 Neuropeptide Y signaling and central cardiovascular regulation……………………..14
2. Specific Aims………………………………………………………….…...16
3. Materials and Methods……………………………………………………..17
3.1 Reagents and chemicals………………………………………………………….……17
3.2 Animals…………………………………………………………………………..……18
3.3 Experimental Procedures……………………………………………………………...18
3.4 Microinjections of drugs………………………………………………………………20
3.5 Western Blot Analysis…………………………………………………………….…...21
3.6 Immunohistochemistry (IHC)…………………………………………………………23
3.7 Immunohistochemistry cell count……………………………………………………..25
3.8 Statistical Analysis…………………………………………………………………….25
4. Results………………………………………………………………….…...26
4.1 The cardiovascular effects of NPY , NPYY1 receptor agonist and NPYY2 receptor agonist microinjection into NTS………………………………………………………26
4.2 Prior administration of BIBP 3226 significantly attenuated the cardiovascular effect of NPY in the NTS of WKY rats………………………………………….….……..……26
4.3 Prior administration of pertussis toxin significantly attenuated the cardiovascular effect of NPY in the NTS of WKY rats………………………………………………………27
4.4 PI3K-Akt pathway and NPY mediated cardiovascular effects in WKY rats……….…28
4.4.1 Prior administration of LY 294002 did not attenuate the cardiovascular effect of NPY in the NTS of WKY rats………………………………….………………….28
4.4.2 NPY and NPYY1 receptor agonist and NPYY2 receptor agonist did not induce Akt phosphorylation in the NTS of WKY rats……………………….………………...28
4.5 MAPK pathway and NPY mediated cardiovascular effects in WKY rats………...…..29
4.5.1 Prior administration of PD98059 significantly attenuated the cardiovascular effect of NPY in the NTS of WKY rats…………………………………………………..29
4.5.2 Attenuation of NPY induced ERKThr202/Tyr204 phosphorylation by BIBP 3226 in the NTS of WKY rats………………………………………………………………….29
4.5.3 NPY Y1 receptor involved in the signal pathway of NPY in the modulation of cardiovascular functions…………………………………………..…..….………..30
4.5.4 Attenuation of NPY induced ERKThr202/Tyr204 phosphorylation by PD98059 in the NTS of WKY rats………….…………………………………………..…………..31
4.5.5 Attenuation of NPY induced in situ ERKThr202/Tyr204 phosphorylation by PD98059 in the NTS of WKY rats……………………………….………………………..……32
4.6 RSK and NPY mediated cardiovascular effects in WKY rats…………..……………..33
4.6.1 NPY and NPY Y1 receptor agonist involved in the signal pathway of NPY induced RSK phophorylation……………………………………….………………………33
4.6.2 NPY induced in situ phospho-p90RSKThr359/Ser363 phosphorylation in the NTS of WKY rats………………….……………………………………………………….34
4.7 NOS-NO pathway and NPY mediated cardiovascular effects in WKY rats……..……34
4.7.1 Prior administration of L-NAME significantly attenuated the cardiovascular effect of NPY in the NTS of WKY rats……………………………………………….….34
4.7.2 Prior administration of 7-NI did not attenuated the cardiovascular effect of NPY in the NTS of WKY rats…………………………………….………….…………….35
4.7.3 Prior administration of Vinyl-L-NIO did not attenuate the cardiovascular effect of NPY in the NTS of WKY rats……………………………….……………….……35
4.7.4 Prior administration of L-NIO significantly attenuated the cardiovascular effect of NPY in the NTS of WKY rats…………………………….……………………….36
4.7.5 Prior administration of L-NIO significantly attenuated the cardiovascular effect of NPY Y1 receptor agonist in the NTS of WKY rats……………….………….……36

4.7.6 Prior administration of L-NIO significantly attenuate the cardiovascular effect of NPY Y2 receptor agonist in the NTS of WKY rats………….…………….………37
4.7.7 Time course of NPY-stimulated ERK phosphorlation, RSK phosphorylation, eNOS phosphrylation in the NTS of WKY rats………………………….………….……37
4.7.8 NPY induced in situ phospho-eNOSSer1177 phosphorylation in the NTS of WKY rats……………………….………………………………………..……….………38
4.7.9 NPY did not induce in situ phospho-nNOSSer1416 phosphorylation in the NTS of WKY rats………………………………….……………………...…………….….38
5. Dissussion……………………………………………………………….…40
6. Conclusion…………………………………………………...………….....47
7. Future Perspectives…………………………………………………….…..48
8. References……………………………………………………………….…51
9. Appendix…………………………………………………………………..110
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