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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 姜至剛 | |
| dc.contributor.author | Cai-Qin Xiao | en |
| dc.contributor.author | 肖彩琴 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:40:49Z | - |
| dc.date.available | 2021-08-30 | |
| dc.date.copyright | 2018-08-30 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-06 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70847 | - |
| dc.description.abstract | 心血管疾病（cardiovascular diseases, CVDs）是目前全球最常見的死因之一，且罹患心血管相關疾病的人口呈逐年增長的趨勢，而主要引起這些疾病的危險因子包括：飲食，肥胖，高血壓，高血脂和糖尿病等。其中，飲食中的飽和脂肪酸（saturated fatty acids）被認為是引發心血管疾病的重要元兇。血液中過量的飽和脂肪酸會堆積在非脂肪組織進而造成組織病變，又稱為脂質毒性（lipotoxicity）。過去有許多研究指出血管內皮細胞的功能異常（endothelial dysfunction）是引發心血管疾病和心血管相關併發症的病理開端。另一方面，最近十年有諸多研究發現未折疊蛋白反應（unfolded protein response, UPR）在心血管疾病中扮演重要的角色。IRE1α-XBP1s 是UPR中主要的分支之一，在動物實驗中證實XBP1s （spliced X-box-binding protein 1）的缺失會影響血管新生（angiogenesis）。最新一項臨床研究顯示增加健康受試者血中的遊離脂肪酸會誘導保護性UPR反應，其中XBP1s表現量快速增加。但目前針對XBP1s在脂質毒性引起的早期內皮功能異常中扮演的角色和調控機制仍未被釐清。本研究利用一種典型的病理性飽和脂肪酸棕櫚酸（palmitic acid, PA）來誘導臍靜脈內皮細胞（Human umbilical vein endothelial cells, HUVECs）功能異常，從而探討XBP1s在此過程中的調控角色。實驗結果顯示內皮細胞在0.25 mM PA濃度下不會影響細胞存活率，並且PA處理的內皮細胞中XBP1s mRNA與蛋白質的表現量顯著增加。但是，在傷口癒合實驗和成管實驗結果顯示在 0.25 mM PA曝露下內皮細胞功能受到顯著影響。接著我們借由4μ8C（一種選擇性IRE1抑制劑）和shRNA抑制細胞中XBP1s 的表現，以進一步研究XBP1s在PA誘導的內皮功能異常中扮演的調控角色。結果顯示內皮細胞在4μ8C或shXBP1s處理能明顯降低PA誘發的 XBP1s的表達。同時，XBP1s之後抑制，血管內皮功能受到更嚴重的影響。另外, 實驗進一步發現0.25 mM PA不會影響eNOS (endothelial nitric oxide synthase) 表達，但抑制內皮細胞中XBP1s 的表現後，eNOS 的mRNA 穩定性和蛋白質表現也隨之顯著降低。總結，本實驗證明作為適應性UPR路徑中的訊號傳遞分子XBP1s在內皮細胞具有對抗脂質毒性的能力，未來有可能作為預防脂毒性誘導的心血管疾病的治療策略。 | zh_TW |
| dc.description.abstract | Cardiovascular diseases (CVDs) account for the major causes of mortality all over the world. Recently, saturated free fatty acids (FFA) are strongly correlated with metabolic syndromes and are well-known risk factors of CVDs. The accumulation of excess FFA in non-adipose tissue causes lipotoxicity. Endothelial dysfunction is suggested as the first step in multiple CVDs progression. On the anther hand, the unfolded protein response (UPR) initiate three pathways in response to the endoplasmic reticulum (ER) stress, which promote cell survival and restore cellular homeostasis. The IRE1α-XBP1 pathway axis is one of the major branches of adaptive UPR. Briefly, phosphorylated IRE1 has endoribonuclease activity to splice X-box binding protein 1 (XBP1) mRNA alternatively. Spliced XBP-1 (XBP1s) is a stress-inducible transcription factor that is essential for cell survival under stress conditions. A recent clinical study reported improved FFA induce the adaptive UPR with increased XBP1s expression in endothelial cells. Nevertheless, the role of XBP1s in the regulation of endothelial function and the underlying mechanism are still unclear. The aim of this study was to investigate potential regulatory mechanisms of XBP1s in endothelial function under the exposure of palmitic acid (PA), a typical pathological FFA. The impact of PA on endothelial function was evaluated by cell proliferation, wound healing and tube formation assays. Our preliminary results showed that PA did not compromise cell viability at the concentration of 0.25mM, and the XBP1s protein and mRNA level was significantly increased in PA-treated human umbilical vein endothelial cells (HUVECs). Furthermore, as expected, PA revealed anti-angiogenicity in wound healing and tube formation. We then treated cells with 4μ8C, an IRE1 RNase inhibitor which selectively inactivates XBP1 splicing, or lentivirus-shXBP1s to investigate whether XBP1s involved in PA-induced endothelial dysfunction. The data showed that both 4μ8C and lentivirus-shXBP1s treatment remarkably decreased XBP1s mRNA and protein in PA-treated HUVECs, and retarded cell migration and tube formation, and also affected the expression of eNOS protein and mRNA stability. Database analysis indicated that eNOS is a possible target gene of XBP1s. Taken together, we demonstrated that XBP1s, a critical adaptive UPR signaling, probably exert a protective role to against lipotoxicity. It might be a new protective therapy to prevent lipotoxiciy-induced CVDs. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:40:49Z (GMT). No. of bitstreams: 1 ntu-107-R05447013-1.pdf: 2591225 bytes, checksum: a8f1fb08b8a71d956e0a4c23d02ba818 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 口試委員審定書 I
誌謝 II Content IV 中文摘要 VI Abstract VIII Abbreviations X 1. Introduction 1 1.1 Cardiovascular Diseases 1 1.2 Lipotoxicity 1 1.2.1 Free Fatty Acids and Palmitic acid 2 1.3 Lipotoxicity and cardiovascular diseases 3 1.4 Mechanisms of Lipotoxicity in endothelial dysfunction 4 1.4.1 Endothelial nitric oxide synthase 5 1.4.2 Endothelial cell migration 6 1.5 Endoplasmic reticulum stress and unfolded protein response 6 1.5.1 XBP1s in cardiovascular disease 9 2. Aim 10 3. Materials and methods 11 3.1 Cell culture 11 3.2 Preparation of Bovine Serum Albumin (BSA)-Conjugated Palmitate 11 3.3 Western blotting analysis 12 3.4 Wound healing migration assay 13 3.5 Tube formation assay 14 3.6 Total RNA extraction and cDNA synthesis 15 3.7 Quantitative Real-time Polymerase Chain Reaction (qRT- PCR) 15 3.8 MTS Assay 16 3.9 Lentivirus production 17 3.10 shRNA lentiviral infection 18 3.11 Oil Red O Staining 18 3.12 Statistical Analysis 19 4. Results 20 4.1 BSA-conjugated PA induces ER stress in HUVECs 20 4.2 The 0.25mM PA does not affect the survival of HUVECs 21 4.3 PA impacts endothelial function of HUVECs 21 4.4 XBP1s plays a protective role in endothelial function under PA exposure 22 4.5 XBP1 deficiency affects endothelial function 23 4.6 Silencing of XBP1s attenuates the expression of eNOS in HUVECs 24 5. Discussion 26 6. Conclusion 32 7. Future perspectives 33 7.1 Luciferase activity assay 33 7.2 Hindlimb ischemia in endothelial cells specific knockout mice 33 8. References 34 9. Figures and Figure Legends 53 | |
| dc.language.iso | en | |
| dc.subject | 棕櫚酸 | zh_TW |
| dc.subject | 心血管疾病 | zh_TW |
| dc.subject | 脂質毒性 | zh_TW |
| dc.subject | 血管內皮細胞 | zh_TW |
| dc.subject | 未折疊蛋白反應 | zh_TW |
| dc.subject | 內皮細胞型一氧化氮合成? | zh_TW |
| dc.subject | free fatty acids | en |
| dc.subject | palmitic acid | en |
| dc.subject | ER stress | en |
| dc.subject | XBP1 | en |
| dc.subject | endothelial dysfunction | en |
| dc.title | 剪接型XBP1在棕櫚酸引發的血管內皮脂毒性中扮演之角色 | zh_TW |
| dc.title | Roles of spliced XBP1 in palmitic acid-induced endothelial lipotoxicity | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 劉興華,蕭水銀,許美玲 | |
| dc.subject.keyword | 心血管疾病,脂質毒性,血管內皮細胞,未折疊蛋白反應,內皮細胞型一氧化氮合成?,棕櫚酸, | zh_TW |
| dc.subject.keyword | free fatty acids,palmitic acid,ER stress,XBP1,endothelial dysfunction, | en |
| dc.relation.page | 67 | |
| dc.identifier.doi | 10.6342/NTU201802025 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-06 | |
| 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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