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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 康照洲(Jaw-Jou Kang) | |
dc.contributor.author | Yao-Teng Hsu | en |
dc.contributor.author | 許躍騰 | zh_TW |
dc.date.accessioned | 2021-06-13T00:15:52Z | - |
dc.date.available | 2009-08-08 | |
dc.date.copyright | 2007-08-08 | |
dc.date.issued | 2007 | |
dc.date.submitted | 2007-07-27 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/28654 | - |
dc.description.abstract | 吸煙會導致許多不同的血管壁病變,例如血管疾病最重要的病徵-血管內皮細胞的傷害,而香菸煙霧中的PAH也被認為與許多不同的心血管疾病如心肌病變、缺血性心臟病、心衰竭、心肌梗塞、高血壓及粥狀動脈硬化等有很大的關聯性。血管新生是由已經存在的血管生出新血管的過程,在癌症及缺血性心血管疾病都扮演相當重要的角色,而近年的研究顯示香菸煙霧的暴露會導致血管新生的進行受到抑制。苯芘(benzo[a]pyrene, B[a]P)是香菸煙霧中一種主要的PAH,根據報導B[a]P的含量高達10-50 ng/每支香煙,也被證實會對血管壁的內皮細胞造成傷害;所以我們想要去探討B[a]P對血管新生的影響。在管狀形成分析的部分,我們發現臍靜脈內皮細胞經不同濃度( 0.33~10μM )的B[a]P前處理24小時後會造成細胞的管狀形成作用受到影響,而且前處理B[a]P的細胞對bFGF或VEGF所誘導的管狀形成作用也有劑量相關效應的抑制作用。此外,在細胞移行方面,我們發現B[a]P的前處理也會抑制由bFGF或VEGF所誘導的細胞趨化作用。綜觀以上結果,我們認為B[a]P可以去抑制體外的模式下血管新生作用,而這樣的抗血管新生作用可能導因於對內皮細胞移行作用的抑制。
血管新生可以受到許多來自於生長因子受器及胞外基質受器的訊息所調控,而近年的研究也顯示ERK的活化不但會受到許多促血管新生因子的誘導,而且跟內皮細胞的移型及管狀形成作用有很大的關係。因此,我們近一步去探討B[a]P對人類臍靜脈內皮細胞的ERK活化及細胞表面的integrin αvβ3表現是否有影響。我們發現B[a]P的前處理不但會抑制由bFGF及VEGF所誘導的ERK活化,也會抑制bFGF所誘導的細胞表面integrin αvβ3表現。此外,我們還發現AhR 拮抗劑alpha-naphthoflavon (alpha-NF)的處理會有效的阻礙B[a]P前處理對bFGF所誘導的ERK活化所產生的抑制作用,所以我們認為B[a]P對生長因子所誘導的ERK活化的抑制作用是透過AhR來達成的。總結以上的結果,B[a]P在體外的模式下所抑制的內皮細胞血管新生作用可能是因為它抑制了需要ERK活化的訊息傳遞路徑以及細胞膜表面的integrin αvβ3表現,進而抑制了內皮細胞的移行作用而達成。 | zh_TW |
dc.description.abstract | Smoking induces many pathologic changes in the blood vessel wall, including endothelial cell injury, an event that is critical in the pathogenesis of vascular disease. It has been reported that polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are strongly involved in the pathogenesis of cardiovascular diseases such as cardiomyopathy, ischemic heart diseases, heart failure, myocardial infarction, hypertension, and atherosclerosis. Angiogenesis, the process by which new blood vessels develop from pre-existing blood vessels, impacts significantly on many important disease states including cancer and ischemic cardiovascular disease. Recent studies have been show cigarette smoke exposure can impair angiogenesis. The PAH-benzo[a]pyrene is one smoke-related compound that has been associated with endothelial damage in blood vessels, and it has also been reported that B[a]P concentration is as high as 10-50 ng per cigarette. Thus, the results of these studies promote us to investigate the effects of B[a]P on angiogenesis. In this study, we found that in vitro tube formation of HUVECs was affected by pretreatment with B[a]P in various concentrations ( 0.33~10μM ) for 24 hr and basic fibroblast growth factor ( bFGF )-/ vascular endothelial growth factor ( VEGF )-induced tube formation was inhibited dose-dependently in B[a]P pretreated HUVECs. B[a]P also inhibited the bFGF-/VEGF-induced chemotactic motility in cell migration assay. Taken together, B[a]P can inhibit angiogenesis in an in vitro system and this antiangiogenic activity might be due to the inhibition of endothelial cell migration.
Angiogenesis is regulated by signals derived from receptors for both growth factors and ECM molecules. Recent studies have shown that activation of ERKs is closely involved in the migration or tubular-like formation of endothelial cells and induced by various angiogenic factors. Therefore, we want further to investigate effects of B[a]P on HUVECs ERK activation and cell surface integrin αvβ3 expression. We found bFGF-/VEGF-induced ERK activation and bFGF-induced cell surface integrin αvβ3 expression were suppressed in B[a]P pretreated HUVECs. Interestingly, the inhibition of bFGF-induced ERK activation by B[a]P was eliminated to a greater extent by aryl hydrocarbon receptor( AhR ) antagonists, alpha-naphthoflavon ( alpha-NF ). Therefore, we thought that AhR might involved in inhibition of growth factor-induced ERK activation by B[a]P. In conclusion, these results indicate that the in vitro inhibition of B[a]P on endothelial cell angiogenesis might be due to suppression of mitogen-activated protein kinase ERK-dependent pathway and cell surface integrin αvβ3 expression, and then further suppresses endothelial cell migration. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T00:15:52Z (GMT). No. of bitstreams: 1 ntu-96-R94447005-1.pdf: 1201876 bytes, checksum: 3aec6d8724487c721fe031c581f164b6 (MD5) Previous issue date: 2007 | en |
dc.description.tableofcontents | 縮寫表………………………………………………………………………………….IV
附圖目錄………………………………………………………………………………..V 中文摘要……………………………………………………………………………….VI 英文摘要……………………………………………………………………………..VIII 第一章 序論 (Introduction)…………………………………………………………...1 1-1 文獻回顧………………………………………………………………………….1 1-1-1 血管新生…………………………………………………………………………1 1-1-2 血管內皮細胞……………………………………………………………………2 1-1-3 血管新生的調控…………………………………………………………………3 1-1-4 多環芳香烴與苯芘(benzo[a]pyrene)…………………………………………….6 1-1-5 多環芳香烴與心血管疾病(cardiovascular disease, CVD)………………………7 1-1-6 多環芳香烴與血管新生………………………………………………………….9 1-2 研究動機………………………………………………………………………..11 第二章 實驗材料與方法 (Materials and Methods) 2-1 實驗材料………………………………………………………………………..12 2-1-1 實驗藥品………………………………………………………………………...12 2-1-2 抗體與試劑……………………………………………………………………...12 2-2 實驗方法………………………………………………………………………..13 2-2-1 人類臍靜脈內皮細胞 (human umbilical vein endothelial cells, HUVECs)的分離與培養……………………………………………………………………….13 2-2-2 管狀形成實驗 (Tube formation assay)………………………………………...14 2-2-3 細胞毒性測試 (MTT cytotoxic analysis)…………………………………….15 2-2-4 細胞移行實驗 (Cell migration assay)………………………………………….15 2-2-5 西方墨點法 (Western blot analysis)…………………………………………....15 2-2-6 細胞表面整合素表現的分析…………………………………………………..16 2-2-7 雞胚胎尿絨毛膜試驗(Chorioallantoic membrane assay, CAM assay)………..17 2-2-8統計分析(Statistic analysis)……………………………………………………..18 第三章 實驗結果 (Results)…………………………………………………………..19 3-1 多環芳香烴(polycyclic aromatic hydrocarbons, PAHs)對人類臍靜脈內皮細胞管狀形成作用的影響………………………………………………………….......19 3-2 苯芘(benzo[a]pyrene, B[a]P )抑制人類臍靜脈內皮細胞管狀形成作用............19 3-3 苯芘(benzo[a]pyrene, B[a]P)對人類臍靜脈內皮細胞無細胞毒(cytotoxicity)...20 3-4 苯芘(benzo[a]pyrene, B[a]P )對bFGF與VEGF所誘導的人類臍靜脈內皮細胞 管狀形成、細胞增生及細胞移行作用的影響…………………………………21 3-5 苯芘(benzo[a]pyrene, B[a]P )抑制由bFGF及VEGF所誘導Erk活化……….23 3-6 苯芘(benzo[a]pyrene, B[a]P )不影響由bFGF及VEGF所誘導Akt活化……..24 3-7 苯芘(benzo[a]pyrene, B[a]P )抑制細胞膜上由bFGF所誘導表現的integrin avb3…………………………………………………………………………….26 3-8 苯芘(benzo[a]pyrene, B[a]P )抑制由bFGF所誘導的Erk活化是透過AhR.....27 第四章 討論 (Discussions)...........................................................................................29 4-1 多環芳香烴對(polycyclic aromatic hydrocarbons, PAHs)內皮細胞血管新生作用的影響……………………………………………………………………….29 4-2 苯芘(benzo[a]pyrene, B[a]P )會抑制由生長因子所誘導的血管新生作用……29 4-3 苯芘(benzo[a]pyrene, B[a]P )會抑制由生長因子所誘導的Erk活化但不影響生長因子所誘導的Akt活化……………………………………………………...32 4-4 苯芘(benzo[a]pyrene, B[a]P )會抑制由bFGF所誘導的integrin avb3表現在細胞膜上…………………………………………………………………………...32 4-5 AhR的拮抗劑(aryl hydrocarbon receptor antagonists)會阻礙苯芘(benzo[a]pyrene, B[a]P )對bFGF所誘導的Erk活化的抑制作用…………..34 4-6 苯芘(benzo[a]pyrene, B[a]P ) 對胞外基質降解作用的影響................................35 第五章 結論 (conclusion)…………………………………………………………….37 第六章 參考文獻 (References)………………………………………………………39 第七章 圖集 (Figures)..................................................................................................60 | |
dc.language.iso | zh-TW | |
dc.title | 苯芘對纖維母細胞生長因子及血管內皮細胞生長因子所誘導之血管新生的抑制作用 | zh_TW |
dc.title | Inhibition of Benzo[a]pyrene on bFGF- and VEGF-induced Angiogenesis | en |
dc.type | Thesis | |
dc.date.schoolyear | 95-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 彭福佐,許金玉 | |
dc.subject.keyword | 苯芘,血管新生,臍靜脈血管內皮細胞, | zh_TW |
dc.subject.keyword | Benzo[a]pyrene,Angiogenesis,HUVEC, | en |
dc.relation.page | 79 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2007-07-27 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 毒理學研究所 | zh_TW |
顯示於系所單位: | 毒理學研究所 |
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