請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19828
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳玉怜(Yuh-Lien Chen) | |
dc.contributor.author | Zhe-Yu Shi | en |
dc.contributor.author | 石哲宇 | zh_TW |
dc.date.accessioned | 2021-06-08T02:21:37Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-08-19 | |
dc.identifier.citation | 1. Zhou X, Nicoletti A, Elhage R, Hansson GK. Transfer of cd4(+) t cells aggravates atherosclerosis in immunodeficient apolipoprotein e knockout mice. Circulation. 2000;102:2919-2922
2. Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of cd40: Induction of collagenase, stromelysin, and tissue factor. Circulation. 1997;96:396-399 3. Bavendiek U, Libby P, Kilbride M, Reynolds R, Mackman N, Schonbeck U. Induction of tissue factor expression in human endothelial cells by cd40 ligand is mediated via activator protein 1, nuclear factor kappa b, and egr-1. The Journal of biological chemistry. 2002;277:25032-25039 4. Schonbeck U, Mach F, Sukhova GK, Herman M, Graber P, Kehry MR, Libby P. Cd40 ligation induces tissue factor expression in human vascular smooth muscle cells. The American journal of pathology. 2000;156:7-14 5. Manduteanu I, Simionescu M. Inflammation in atherosclerosis: A cause or a result of vascular disorders? Journal of cellular and molecular medicine. 2012;16:1978-1990 6. Choi MS, Lee WH, Kwon EY, Kang MA, Lee MK, Park YB, Jeon SM. Effects of soy pinitol on the pro-inflammatory cytokines and scavenger receptors in oxidized low-density lipoprotein-treated thp-1 macrophages. Journal of medicinal food. 2007;10:594-601 7. Chrousos GP, Calabrese JR, Avgerinos P, Kling MA, Rubinow D, Oldfield EH, Schuermeyer T, Kellner CH, Cutler GB, Jr., Loriaux DL, et al. Corticotropin releasing factor: Basic studies and clinical applications. Progress in neuro-psychopharmacology biological psychiatry. 1985;9:349-359 8. Old LJ. Tumor necrosis factor (tnf). Science. 1985;230:630-632 9. Raines EW, Ferri N. Thematic review series: The immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. Journal of lipid research. 2005;46:1081-1092 10. Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: Pathobiological mechanisms and clinical implications. Circulation research. 2006;99:1044-1059 11. Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. The Journal of clinical investigation. 1993;91:1800-1809 12. Goettsch C, Rauner M, Hamann C, Sinningen K, Hempel U, Bornstein SR, Hofbauer LC. Nuclear factor of activated t cells mediates oxidised ldl-induced calcification of vascular smooth muscle cells. Diabetologia. 2011;54:2690-2701 13. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell. 1994;76:301-314 14. Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN. Increase in the adhesion molecule p-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1. The American journal of pathology. 1994;144:952-961 15. Davies MJ, Gordon JL, Gearing AJ, Pigott R, Woolf N, Katz D, Kyriakopoulos A. The expression of the adhesion molecules icam-1, vcam-1, pecam, and e-selectin in human atherosclerosis. The Journal of pathology. 1993;171:223-229 16. Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (cd54) gene expression. Journal of leukocyte biology. 1999;66:876-888 17. Manka DR, Wiegman P, Din S, Sanders JM, Green SA, Gimple LW, Ragosta M, Powers ER, Ley K, Sarembock IJ. Arterial injury increases expression of inflammatory adhesion molecules in the carotid arteries of apolipoprotein-e-deficient mice. Journal of vascular research. 1999;36:372-378 18. O'Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD, et al. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis. The Journal of clinical investigation. 1993;92:945-951 19. O'Brien KD, McDonald TO, Chait A, Allen MD, Alpers CE. Neovascular expression of e-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation. 1996;93:672-682 20. Allen S, Khan S, Al-Mohanna F, Batten P, Yacoub M. Native low density lipoprotein-induced calcium transients trigger vcam-1 and e-selectin expression in cultured human vascular endothelial cells. The Journal of clinical investigation. 1998;101:1064-1075 21. Coll T, Eyre E, Rodriguez-Calvo R, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. The Journal of biological chemistry. 2008;283:11107-11116 22. Koyama T, Kume S, Koya D, Araki S, Isshiki K, Chin-Kanasaki M, Sugimoto T, Haneda M, Sugaya T, Kashiwagi A, Maegawa H, Uzu T. Sirt3 attenuates palmitate-induced ros production and inflammation in proximal tubular cells. Free radical biology medicine. 2011;51:1258-1267 23. Bierhaus A, Schiekofer S, Schwaninger M, Andrassy M, Humpert PM, Chen J, Hong M, Luther T, Henle T, Kloting I, Morcos M, Hofmann M, Tritschler H, Weigle B, Kasper M, Smith M, Perry G, Schmidt AM, Stern DM, Haring HU, Schleicher E, Nawroth PP. Diabetes-associated sustained activation of the transcription factor nuclear factor-kappab. Diabetes. 2001;50:2792-2808 24. Gao Y, Zhang J, Li G, Xu H, Yi Y, Wu Q, Song M, Bee YM, Huang L, Tan M, Liang S. Protection of vascular endothelial cells from high glucose-induced cytotoxicity by emodin. Biochemical pharmacology. 2015;94:39-45 25. Jin F, Jiang S, Yang D, Zhang X, Yang Y, Zhang Y, Li K, Ma S. Acipimox attenuates atherosclerosis and enhances plaque stability in apoe-deficient mice fed a palmitate-rich diet. Biochemical and biophysical research communications. 2012;428:86-92 26. Ceriello A. The post-prandial state and cardiovascular disease: Relevance to diabetes mellitus. Diabetes/metabolism research and reviews. 2000;16:125-132 27. Ceriello A. Acute hyperglycaemia and oxidative stress generation. Diabetic medicine : a journal of the British Diabetic Association. 1997;14 Suppl 3:S45-49 28. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiological reviews. 2001;81:807-869 29. Paul A, Wilson S, Belham CM, Robinson CJ, Scott PH, Gould GW, Plevin R. Stress-activated protein kinases: Activation, regulation and function. Cellular signalling. 1997;9:403-410 30. English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S, Cobb MH. New insights into the control of map kinase pathways. Experimental cell research. 1999;253:255-270 31. Chang L, Karin M. Mammalian map kinase signalling cascades. Nature. 2001;410:37-40 32. Kumar A, Middleton A, Chambers TC, Mehta KD. Differential roles of extracellular signal-regulated kinase-1/2 and p38(mapk) in interleukin-1beta- and tumor necrosis factor-alpha-induced low density lipoprotein receptor expression in hepg2 cells. The Journal of biological chemistry. 1998;273:15742-15748 33. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, Smith R, Lessnick SL, Sahasrabudhe S, Stockwell BR. Ras-raf-mek-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447:864-868 34. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: Inhibition of nf-kappa b activity through induction of i kappa b synthesis. Science. 1995;270:286-290 35. Geng Y, Valbracht J, Lotz M. Selective activation of the mitogen-activated protein kinase subgroups c-jun nh2 terminal kinase and p38 by il-1 and tnf in human articular chondrocytes. The Journal of clinical investigation. 1996;98:2425-2430 36. Kyriakis JM, Avruch J. Sounding the alarm: Protein kinase cascades activated by stress and inflammation. The Journal of biological chemistry. 1996;271:24313-24316 37. Woodgett JR, Avruch J, Kyriakis J. The stress activated protein kinase pathway. Cancer surveys. 1996;27:127-138 38. Ip YT, Davis RJ. Signal transduction by the c-jun n-terminal kinase (jnk)--from inflammation to development. Current opinion in cell biology. 1998;10:205-219 39. Hibi M, Lin A, Smeal T, Minden A, Karin M. Identification of an oncoprotein- and uv-responsive protein kinase that binds and potentiates the c-jun activation domain. Genes development. 1993;7:2135-2148 40. Hocevar BA, Brown TL, Howe PH. Tgf-beta induces fibronectin synthesis through a c-jun n-terminal kinase-dependent, smad4-independent pathway. The EMBO journal. 1999;18:1345-1356 41. Read MA, Whitley MZ, Gupta S, Pierce JW, Best J, Davis RJ, Collins T. Tumor necrosis factor alpha-induced e-selectin expression is activated by the nuclear factor-kappab and c-jun n-terminal kinase/p38 mitogen-activated protein kinase pathways. The Journal of biological chemistry. 1997;272:2753-2761 42. Surapisitchat J, Hoefen RJ, Pi X, Yoshizumi M, Yan C, Berk BC. Fluid shear stress inhibits tnf-alpha activation of jnk but not erk1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among mapk family members. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:6476-6481 43. Erdogdu O, Eriksson L, Xu H, Sjoholm A, Zhang Q, Nystrom T. Exendin-4 protects endothelial cells from lipoapoptosis by pka, pi3k, enos, p38 mapk, and jnk pathways. Journal of molecular endocrinology. 2013;50:229-241 44. Ma J, Hart GW. O-glcnac profiling: From proteins to proteomes. Clinical proteomics. 2014;11:8 45. Comer FI, Hart GW. Reciprocity between o-glcnac and o-phosphate on the carboxyl terminal domain of rna polymerase ii. Biochemistry. 2001;40:7845-7852 46. Zhang F, Su K, Yang X, Bowe DB, Paterson AJ, Kudlow JE. O-glcnac modification is an endogenous inhibitor of the proteasome. Cell. 2003;115:715-725 47. Zhang F, Hu Y, Huang P, Toleman CA, Paterson AJ, Kudlow JE. Proteasome function is regulated by cyclic amp-dependent protein kinase through phosphorylation of rpt6. The Journal of biological chemistry. 2007;282:22460-22471 48. Zachara NE, O'Donnell N, Cheung WD, Mercer JJ, Marth JD, Hart GW. Dynamic o-glcnac modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. The Journal of biological chemistry. 2004;279:30133-30142 49. Love DC, Kochan J, Cathey RL, Shin SH, Hanover JA. Mitochondrial and nucleocytoplasmic targeting of o-linked glcnac transferase. Journal of cell science. 2003;116:647-654 50. Vasudevan KM, Garraway LA. Akt signaling in physiology and disease. Current topics in microbiology and immunology. 2010;347:105-133 51. Bond MR, Hanover JA. O-glcnac cycling: A link between metabolism and chronic disease. Annual review of nutrition. 2013;33:205-229 52. Baldwin AS, Jr. The nf-kappa b and i kappa b proteins: New discoveries and insights. Annual review of immunology. 1996;14:649-683 53. Greene WC, Chen LF. Regulation of nf-kappab action by reversible acetylation. Novartis Foundation symposium. 2004;259:208-217; discussion 218-225 54. James LR, Tang D, Ingram A, Ly H, Thai K, Cai L, Scholey JW. Flux through the hexosamine pathway is a determinant of nuclear factor kappab- dependent promoter activation. Diabetes. 2002;51:1146-1156 55. Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM. Phosphoinositide signalling links o-glcnac transferase to insulin resistance. Nature. 2008;451:964-969 56. Chen LF, Mu Y, Greene WC. Acetylation of rela at discrete sites regulates distinct nuclear functions of nf-kappab. The EMBO journal. 2002;21:6539-6548 57. Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, Benkirane M. Post-activation turn-off of nf-kappa b-dependent transcription is regulated by acetylation of p65. The Journal of biological chemistry. 2003;278:2758-2766 58. Allison DF, Wamsley JJ, Kumar M, Li D, Gray LG, Hart GW, Jones DR, Mayo MW. Modification of rela by o-linked n-acetylglucosamine links glucose metabolism to nf-kappab acetylation and transcription. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:16888-16893 59. Golks A, Tran TT, Goetschy JF, Guerini D. Requirement for o-linked n-acetylglucosaminyltransferase in lymphocytes activation. The EMBO journal. 2007;26:4368-4379 60. Zou L, Yang S, Hu S, Chaudry IH, Marchase RB, Chatham JC. The protective effects of pugnac on cardiac function after trauma-hemorrhage are mediated via increased protein o-glcnac levels. Shock. 2007;27:402-408 61. Zou L, Yang S, Champattanachai V, Hu S, Chaudry IH, Marchase RB, Chatham JC. Glucosamine improves cardiac function following trauma-hemorrhage by increased protein o-glcnacylation and attenuation of nf-{kappa}b signaling. American journal of physiology. Heart and circulatory physiology. 2009;296:H515-523 62. Xing D, Feng W, Not LG, Miller AP, Zhang Y, Chen YF, Majid-Hassan E, Chatham JC, Oparil S. Increased protein o-glcnac modification inhibits inflammatory and neointimal responses to acute endoluminal arterial injury. American journal of physiology. Heart and circulatory physiology. 2008;295:H335-342 63. Hilgers RH, Xing D, Gong K, Chen YF, Chatham JC, Oparil S. Acute o-glcnacylation prevents inflammation-induced vascular dysfunction. American journal of physiology. Heart and circulatory physiology. 2012;303:H513-522 64. Mita T, Otsuka A, Azuma K, Uchida T, Ogihara T, Fujitani Y, Hirose T, Mitsumata M, Kawamori R, Watada H. Swings in blood glucose levels accelerate atherogenesis in apolipoprotein e-deficient mice. Biochemical and biophysical research communications. 2007;358:679-685 65. Eriksson L, Nystrom T. Activation of amp-activated protein kinase by metformin protects human coronary artery endothelial cells against diabetic lipoapoptosis. Cardiovascular diabetology. 2014;13:152 66. Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature. 1993;362:801-809 67. Choi SE, Jang HJ, Kang Y, Jung JG, Han SJ, Kim HJ, Kim DJ, Lee KW. Atherosclerosis induced by a high-fat diet is alleviated by lithium chloride via reduction of vcam expression in apoe-deficient mice. Vascular pharmacology. 2010;53:264-272 68. Chai W, Liu Z. P38 mitogen-activated protein kinase mediates palmitate-induced apoptosis but not inhibitor of nuclear factor-kappab degradation in human coronary artery endothelial cells. Endocrinology. 2007;148:1622-1628 69. Cacicedo JM, Yagihashi N, Keaney JF, Jr., Ruderman NB, Ido Y. Ampk inhibits fatty acid-induced increases in nf-kappab transactivation in cultured human umbilical vein endothelial cells. Biochemical and biophysical research communications. 2004;324:1204-1209 70. Bond MR, Hanover JA. A little sugar goes a long way: The cell biology of o-glcnac. The Journal of cell biology. 2015;208:869-880 71. Yang WH, Park SY, Nam HW, Kim do H, Kang JG, Kang ES, Kim YS, Lee HC, Kim KS, Cho JW. Nfkappab activation is associated with its o-glcnacylation state under hyperglycemic conditions. Proceedings of the National Academy of Sciences of the United States of America. 2008;105:17345-17350 72. Baudoin L, Issad T. O-glcnacylation and inflammation: A vast territory to explore. Frontiers in endocrinology. 2014;5:235 73. Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. Jama. 2006;295:1681-1687 74. Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: The role of protein kinase c and nad(p)h-oxidase activation. Diabetes. 2003;52:2795-2804 75. Risso A, Mercuri F, Quagliaro L, Damante G, Ceriello A. Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. American journal of physiology. Endocrinology and metabolism. 2001;281:E924-930 76. Azuma K, Watada H, Niihashi M, Otsuka A, Sato F, Kawasumi M, Shimada S, Tanaka Y, Kawamori R, Mitsumata M. A new en face method is useful to quantitate endothelial damage in vivo. Biochemical and biophysical research communications. 2003;309:384-390 77. Otsuka A, Azuma K, Iesaki T, Sato F, Hirose T, Shimizu T, Tanaka Y, Daida H, Kawamori R, Watada H. Temporary hyperglycaemia provokes monocyte adhesion to endothelial cells in rat thoracic aorta. Diabetologia. 2005;48:2667-2674 78. Azuma K, Kawamori R, Toyofuku Y, Kitahara Y, Sato F, Shimizu T, Miura K, Mine T, Tanaka Y, Mitsumata M, Watada H. Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta. Arteriosclerosis, thrombosis, and vascular biology. 2006;26:2275-2280 79. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. Ikk-beta links inflammation to obesity-induced insulin resistance. Nature medicine. 2005;11:191-198 80. Tanti JF, Jager J. Cellular mechanisms of insulin resistance: Role of stress-regulated serine kinases and insulin receptor substrates (irs) serine phosphorylation. Current opinion in pharmacology. 2009;9:753-762 81. Litvinova LS, Kirienkova EV, Mazunin IO, Vasilenko MA, Fattakhov NS. [insulin resistance pathogenesis in metabolic obesity]. Biomeditsinskaia khimiia. 2015;61:70-82 82. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. Irs-1-mediated inhibition of insulin receptor tyrosine kinase activity in tnf-alpha- and obesity-induced insulin resistance. Science. 1996;271:665-668 83. Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008;134:933-944 84. Moraes RC, Blondet A, Birkenkamp-Demtroeder K, Tirard J, Orntoft TF, Gertler A, Durand P, Naville D, Begeot M. Study of the alteration of gene expression in adipose tissue of diet-induced obese mice by microarray and reverse transcription-polymerase chain reaction analyses. Endocrinology. 2003;144:4773-4782 85. Nadler ST, Stoehr JP, Schueler KL, Tanimoto G, Yandell BS, Attie AD. The expression of adipogenic genes is decreased in obesity and diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America. 2000;97:11371-11376 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19828 | - |
dc.description.abstract | 根據衛生福利部102年度公佈的國人十大死因,心臟疾病、腦血管疾病、糖尿病分別位居第二、三、四名,而高糖高脂飲食常造成這些疾病的主要成因之一。 棕櫚酸為十六碳飽和脂肪酸,是我們飲食攝入飽和脂肪酸的大宗,已有許多研究證實棕櫚酸會造成多種細胞產生發炎反應、細胞凋亡及動脈硬化。在心血管疾病剛形成時,常見血管內皮細胞功能異常,進而導致血管動脈硬化與急性心肌梗塞。內皮細胞功能異常包括發炎、自由基在細胞內堆積,嚴重時常會導致細胞凋亡。而動脈硬化已被證實屬於一種慢性的發炎反應,發炎反應促使內皮細胞黏附因子大量表現,驅使單核球黏附、進入血管管壁以及吞噬囤積在血管管腔的脂質,進而促進動脈硬化斑塊的產生。高糖高脂如何造成內皮細胞發炎及其相關機轉,到目前為止仍相當不清楚,有待研究。因此我們研究的主軸是去探討高糖高脂肪酸對於血管內皮細胞的影響與其機制。我們使用人類臍靜脈內皮細胞做為in vitro的實驗材料,經實驗證實,高糖與高棕櫚酸鈉會誘發內皮細胞顯著表現黏附因子ICAM-1。而針對ICAM-1表現的相關機轉探討時,發現高糖高棕櫚酸鈉會促使內皮細胞p-p38、p-JNK、p-p65的表現量上升。進一步地加入p-38、ERK、JNK、p-65的抑制劑,再加入高糖高棕櫚酸鈉刺激會降低ICAM-1的表現,因此推測高糖高棕櫚酸鈉是經由JNK、p38、ERK與NF-B這三個路徑去誘發ICAM-1的表現。 另外,我們在in vitro實驗中初步發現,在高糖環境下,越高濃度之棕櫚酸鈉,對於人類臍靜脈內皮細胞內之OGT (O-GlcNAc transferase)會有抑制作用;而在高糖環境下,以0.5 mM 棕櫚酸鈉刺激人類臍靜脈內皮細胞後,隨著時間拉長,OGT表現也會明顯地被抑制。OGT為一可進行O-linked glycosylation之酵素,可將特定結構UDP-GlcNAc修飾在細胞核與細胞質蛋白上,這樣的修飾可能造成蛋白的表現改變以及泛素化 (Ubiquitination)。 我們也針對餵食western diet的ApoE-/-小鼠 (實驗組),犧牲取其胸主動脈進行觀察,發現與C57BL/6 (控制組)相比,實驗組老鼠之動脈硬化斑塊非常明顯,並且我們以ICAM-1、VCAM-1、E-selectin、IL-6抗體對發病組與控制組小鼠胸主動脈分別進行免疫組織化學染色。結果發現,與控制組相比,發病組小鼠在動脈硬化斑塊及斑塊周圍之ICAM-1、VCAM-1、E-selectin、IL-6表現相當明顯。在高倍視野下,發現了血管管腔周圍染有CD31 (內皮細胞marker)之動脈內皮細胞也同時有ICAM-1表現,代表形成動脈硬化的過程中,內皮細胞會有慢性發炎的反應產生。在細胞實驗和動物實驗中,我們證實在高糖高脂肪酸環境下會促使黏附因子表現。 | zh_TW |
dc.description.abstract | Population ageing is a foregone conclusion and becomes an important issue in Taiwan. People with higher levels of glucose and fat in diet resulted in the greater risk of cardiovascular diseases. According to the statistics of Ministry of Health and Welfare in 2013, cardiovascular disease, cerebrovascular disease, and diabetes mellitus have remained in the top ten leading causes of death. The previous studies proved that sodium palmitate, a 16-carbon saturated fatty acid, can induce inflammation and apoptosis in many cell types. Either hyperglycemia or hyperlipidemia often bring about vascular dysfunction, including inflammation and accumulation of reactive oxygen spices which lead to up-regulation of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin expression. Furthermore, monocytes adhere to endothelial cells and migrate into subendothelial space to engulf ox-LDL and free fatty acid, then the monocytes were transformed into foam cells. Finally, smooth muscle cells, collagen and foam cells were accumulated in subendothelial space and formed the plaque. Moreover, the atherosclerotic plaques became unstable and they would detach from vascular wall and enter blood circulation, which can seriously lead to acute myocardial infarction and stroke. However, the detailed mechanisms of high glucose and high fatty acid which are involved in the cardiovascular diseases are not clarified. Therefore, we focus on their effects on the expression of ICAM-1 in sodium palmitate plus high glucose-treated human umbilical vein endothelial cells (HUVECs) and their related mechanisms. Palmitate plus high glucose significantly induced ICAM-1 expression as well as the phosphorylation of extracellular-regulated kinase (ERK), p38 MAPK, c-jun N-terminal kinase (JNK), and nuclear factor kappa B (NF-B) in HUVECs. Pretreatment with PD98059 (an ERK1/2 inhibitor), SP600125 (a JNK inhibitor), SB203580 (a p38 inhibitor) and Bay11-7082 (a NF-B inhibitor) significantly reduced ICAM-1 expression under the stimulation of sodium palmitate plus high glucose. Furthermore, we found that cells treated with 0.5 mM sodium palmitate for 24 hours significantly decreased high glucose-induced O-GlcNAc transferase (OGT) expression. In animal studies, we used apoE-/- mice and C57BL/6 mice fed with high -sucrose high-palmitate diet (HSHP diet). The thoracic aorta of apoE-/- mice in HSHP group significantly expressed high level of adhesion molecule (ICAM-1, VCAM-1, E-selectin) and pro-inflammatory cytokine IL-6 by immunohistichemistry. We also find that the co-expression of CD31 (endothelial marker) and ICAM-1 in the endothelial cell, indicating that high-glucose high-palmitate diet will cause the dysfunction of endothelial cells. Based on in vitro and in vivo studies, high palmitate plus high glucose can cause endothelial dysfunction and then lead to the progression of cardiovascular diseases. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:21:37Z (GMT). No. of bitstreams: 1 ntu-104-R02446010-1.pdf: 5205418 bytes, checksum: 61a92afe1da4d3d90c7335d27e3d4b7e (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 中文摘要 v 英文摘要 vii 壹、緒論 一、造成動脈硬化的因子及其危險性 1 二、動脈硬化形成之分子機轉 2 三、動脈硬化與細胞黏附因子之關係 4 四、棕櫚酸鈉與動脈硬化的關係 5 五、高血糖與動脈硬化的關係 6 六、動脈硬化與MAPKs的關係 7 七、O-GlcNAc transferase (OGT)與高血糖之關係 9 八、O-GlcNAc transferase (OGT)與NF-κB之相關性 10 九、研究動機 11 貳、實驗材料 一、儀器設備 13 二、實驗材料與試劑 13 三、實驗用溶液配方 18 參、實驗方法 體外細胞實驗 (In vitro) 一、人類臍靜脈內皮細胞培養 21 二、棕櫚酸鈉配方 21 三、細胞活性分析法 23 四、西方墨點法 23 五、免疫細胞化學染色法 26 動物實驗 (In vivo) 一、動物模式 27 二、高棕櫚酸高蔗糖飼料配方 27 三、胰島素耐受性測試 27 四、組織石蠟包埋 28 五、蘇木精-伊紅染色 28 六、免疫組織化學染色 29 七、數據統計分析 30 肆、實驗結果 以0.5 mM sodium palmitate處理對人類臍靜脈內皮細胞不具毒害性 31 高糖份及 sodium palmitate共同處理使人類臍靜脈內皮細胞ICAM-1蛋白表現顯著上升 31 在正常糖與高糖環境下以sodium palmitate刺激人類臍靜脈內皮細胞會誘發ERK、JNK、p38、NF-B p65的磷酸化 32 高糖環境下以sodium palmitate刺激人類臍靜脈內皮細胞表現ICAM-1是透過MAPKs訊息傳遞 32 高糖環境下以sodium palmitate刺激人類臍靜脈內皮細胞ICAM-1是透過NF-B傳遞 33 高糖會刺激內皮細胞OGT表現量顯著上升,而0.5 mM sodium palmitate會抑制高糖引發的OGT蛋白表現量 33 高糖環境下以sodium palmitate刺激人類臍靜脈內皮細胞會減少OGT蛋白的表現 34 在高糖環境下以sodium palmitate刺激人類臍靜脈內皮細胞不同時間點,發現在第18小時候,OGT蛋白的表現會被sodium palmitate抑制 34 以western diet餵食ApoE-/-小鼠,觀察其體內有動脈硬化斑塊產生,且在病灶處之VCAM-1、E-selectin、IL-6表現量顯著增加 34 以顯微鏡高倍率下觀察餵食western diet之 ApoE-/-小鼠胸主動脈病灶處,發現表現內皮細胞marker CD31的胸主動脈內皮細胞,會強烈表現黏附因子ICAM-1 35 C57BL/6小鼠與ApoE-/-小鼠餵食高棕櫚酸高糖飼料組別的體重輕於餵食控制組飼料的組別 35 與餵食前相比,C57BL/6小鼠餵食高棕櫚酸高蔗糖飼料會引起三酸甘油脂、總膽固醇、游離脂肪酸之血清值顯著升高 36 與餵食前相比,ApoE-/-小鼠餵食高棕櫚酸高蔗糖飼料會引起三酸甘油脂、總膽固醇、游離脂肪酸之血清值顯著升高 36 C57BL/6與ApoE-/-小鼠餵食高棕櫚酸高蔗糖飼料後,會導致其對於胰島素的敏感度提高 37 以高棕櫚酸高蔗糖餵食ApoE-/-小鼠,觀察其體內有動脈硬化斑塊產生,且在病灶處之ICAM-1與OGT表現量與其他組別相比,有顯著的表現 37 伍、討論與結論 38 陸、參考文獻 43 柒、附圖 圖一、以細胞活性分析法觀察 sodium palmitate 對人類臍靜脈內皮細胞存活率的影響 53 圖二、以西方墨點法觀察 sodium palmitate 在正常糖份以及高糖份的環境下,對人類臍靜脈內皮細胞表現ICAM-1的影響 54 圖三、以免疫螢光染色法觀察 sodium palmitate 在正常糖份以及高糖份的環境下,對人類臍靜脈內皮細胞產生ICAM-1的影響 55 圖四、以時間點觀察Sodium palmitate 在正常糖與高糖的環境下,刺激人類臍靜脈內皮細胞是否會誘發MAPKs、 NF-B訊息傳遞 56 圖五、Sodium palmitate 在正常糖份以及高糖份的環境下,刺激人類臍靜脈內皮細胞產生ICAM-1是透過ERK、JNK、P38訊息傳遞 57 圖六、Sodium palmitate 在正常糖份以及高糖份的環境下,刺激人類臍靜脈內皮細胞產生ICAM-1是透過NF-B訊息傳遞 58 圖七、以西方墨點法觀察 sodium palmitate對人類臍靜脈內皮細胞表現OGT蛋白的影響 59 圖八、以免疫螢光染色法觀察 sodium palmitate 在正常糖份以及高糖份的環境下,對人類臍靜脈內皮細胞OGT表現的影響 60 圖九、以西方墨點法觀察在正常糖與高糖的環境下,sodium palmitate在不同時間點對OGT蛋白的影響 61 圖十、以免疫組織化學染色法觀察餵食 western diet對ApoE-/-小鼠胸主動脈的影響 62 圖十一、以免疫組織化學染色法觀察餵食western diet之ApoE-/-小鼠,其胸主動脈強烈表現ICAM-1 63 圖十二、C57BL/6與ApoE-/-小鼠餵食高棕櫚酸高蔗糖飼料與控制組飼料10週,以折線圖表示其體重變化 64 圖十三、以比色法觀察餵食高棕櫚酸高蔗糖飼料(HPHS diet)與控制組飼料(control) 之C57BL/6小鼠血清,其體內血糖、三酸甘油脂、總膽固醇及游離脂肪酸等血清生化數值與餵食前的差異 65 圖十四、以比色法觀察餵食高棕櫚酸高蔗糖飼料(HPHS diet)與控制組飼料(control) 之ApoE-/-小鼠血清,其體內血糖、三酸甘油脂、總膽固醇及游離脂肪酸等血清生化數值與餵食前的差異 66 圖十五、C57BL/6與ApoE-/-小鼠餵食高棕櫚酸高蔗糖飼料後,以胰島素耐受性測試觀察其對胰島素之耐受性 67 圖十六、以免疫組織化學染色法觀察餵食高棕櫚酸高蔗糖飼料對C57BL/6與ApoE-/-小鼠胸主動脈的影響 68 | |
dc.language.iso | zh-TW | |
dc.title | 探討棕櫚酸鈉加上高醣處理對人類臍靜脈內皮細胞與小鼠主動脈表現細胞間黏附因子的作用機制 | zh_TW |
dc.title | The Mechanisms of Sodium Palmitate plus High Glucose on ICAM-1 Expression in Endothelial Cells and Aortas | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 江美治(Meei-Jyh Jiang),李宜達(I-Ta Lee),王懷詩(Hwai-Shi Wang),李江文(Chiang-Weng Lee) | |
dc.subject.keyword | 棕櫚酸鈉,動脈硬化,MAPKs,NF-kB,ICAM-1,OGT, | zh_TW |
dc.subject.keyword | Sodium palmitate,atherosclerosis,MAPKs,NF-kB,ICAM-1,OGT, | en |
dc.relation.page | 68 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2015-08-20 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-104-1.pdf 目前未授權公開取用 | 5.08 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。