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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林甫容 | zh_TW |
| dc.contributor.advisor | Fu-Jung Lin | en |
| dc.contributor.author | 張晏瑜 | zh_TW |
| dc.contributor.author | Yen-Yu Chang | en |
| dc.date.accessioned | 2024-03-04T16:16:18Z | - |
| dc.date.available | 2024-03-05 | - |
| dc.date.copyright | 2024-03-04 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-02-06 | - |
| dc.identifier.citation | 1. Arima, Y. and H. Fukuoka, Developmental origins of health and disease theory in cardiology. J Cardiol, 2020. 76(1): p. 14-17.
2. Chen, S.Y., et al., Maternal hypercholesterolemia exacerbates atherosclerosis lesions in female offspring through potentiating macrophage polarization toward an inflammatory M1 phenotype. J Nutr Biochem, 2021. 90: p. 108575. 3. 曹瑜軒, DNA甲基化在ApoE–/–小鼠動脈粥狀硬化發育程序化之角色, in 生化科技學系. 2021, 國立台灣大學. p. 1-135. 4. Borén, J., et al., Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J Clin Invest, 1998. 101(12): p. 2658-64. 5. Grainger, D.J., et al., Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice. Nature, 1994. 370(6489): p. 460-2. 6. Cyrus, T., et al., Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J Clin Invest, 1999. 103(11): p. 1597-604. 7. Hegele, R.A., Paraoxonase genes and disease. Ann Med, 1999. 31(3): p. 217-24. 8. Shih, D.M., et al., Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem, 2000. 275(23): p. 17527-35. 9. Hofmann, M.A., et al., RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell, 1999. 97(7): p. 889-901. 10. Collins, R.G., et al., P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med, 2000. 191(1): p. 189-94. 11. Dong, Z.M., et al., The combined role of P- and E-selectins in atherosclerosis. J Clin Invest, 1998. 102(1): p. 145-52. 12. Gu, L., et al., Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell, 1998. 2(2): p. 275-81. 13. Boring, L., et al., Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature, 1998. 394(6696): p. 894-7. 14. Moore, K.J., F.J. Sheedy, and E.A. Fisher, Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol, 2013. 13(10): p. 709-21. 15. van Gils, J.M., et al., The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol, 2012. 13(2): p. 136-43. 16. Trogan, E., et al., Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A, 2002. 99(4): p. 2234-9. 17. Gerhard, G.T. and P.B. Duell, Homocysteine and atherosclerosis. Curr Opin Lipidol, 1999. 10(5): p. 417-28. 18. Nathan, L. and G. Chaudhuri, Estrogens and atherosclerosis. Annu Rev Pharmacol Toxicol, 1997. 37: p. 477-515. 19. Yvan-Charvet, L., et al., ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis. Circ Res, 2010. 106(12): p. 1861-9. 20. Newby, A.C., Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev, 2005. 85(1): p. 1-31. 21. Barrett, T.J., Macrophages in Atherosclerosis Regression. Arterioscler Thromb Vasc Biol, 2020. 40(1): p. 20-33. 22. Ivashkiv, L.B., Epigenetic regulation of macrophage polarization and function. Trends Immunol, 2013. 34(5): p. 216-23. 23. Murray, P.J., et al., Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity, 2014. 41(1): p. 14-20. 24. Bisgaard, L.S., et al., Bone marrow-derived and peritoneal macrophages have different inflammatory response to oxLDL and M1/M2 marker expression - implications for atherosclerosis research. Scientific Reports, 2016. 6. 25. Haj-Mirzaian, A., et al., Role of hypothalamic-pituitary adrenal-axis, toll-like receptors, and macrophage polarization in pre-atherosclerotic changes induced by social isolation stress in mice. Scientific Reports, 2021. 11(1). 26. Hamers, A.A., et al., Bone marrow-specific deficiency of nuclear receptor Nur77 enhances atherosclerosis. Circ Res, 2012. 110(3): p. 428-38. 27. Hanna, R.N., et al., The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol, 2011. 12(8): p. 778-85. 28. Hanna, R.N., et al., NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis. Circ Res, 2012. 110(3): p. 416-27. 29. Liao, X., et al., Krüppel-like factor 4 regulates macrophage polarization. J Clin Invest, 2011. 121(7): p. 2736-49. 30. Sharma, N., et al., Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report. Arterioscler Thromb Vasc Biol, 2012. 32(12): p. 2836-8. 31. Calkin, A.C., et al., Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects. Arterioscler Thromb Vasc Biol, 2005. 25(9): p. 1903-9. 32. Babaev, V.R., et al., Macrophage deficiency of Akt2 reduces atherosclerosis in Ldlr null mice. J Lipid Res, 2014. 55(11): p. 2296-308. 33. Feig, J.E., et al., HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci U S A, 2011. 108(17): p. 7166-71. 34. Cardilo-Reis, L., et al., Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol Med, 2012. 4(10): p. 1072-86. 35. Mahley, R.W., Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science, 1988. 240(4852): p. 622-30. 36. Sehayek, E., et al., Apolipoprotein E regulates dietary cholesterol absorption and biliary cholesterol excretion: studies in C57BL/6 apolipoprotein E knockout mice. Proc Natl Acad Sci U S A, 2000. 97(7): p. 3433-7. 37. Piedrahita, J.A., et al., Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci U S A, 1992. 89(10): p. 4471-5. 38. Plump, A.S., et al., Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell, 1992. 71(2): p. 343-53. 39. Jawień, J., P. Nastałek, and R. Korbut, Mouse models of experimental atherosclerosis. J Physiol Pharmacol, 2004. 55(3): p. 503-17. 40. Nakashima, Y., et al., ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb, 1994. 14(1): p. 133-40. 41. Plump, A.S. and J.L. Breslow, Apolipoprotein E and the apolipoprotein E-deficient mouse. Annu Rev Nutr, 1995. 15: p. 495-518. 42. Barker, D.J. and C. Osmond, Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet, 1986. 1(8489): p. 1077-81. 43. Barker, D.J., Fetal origins of coronary heart disease. Bmj, 1995. 311(6998): p. 171-4. 44. Boney, C.M., et al., Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics, 2005. 115(3): p. e290-6. 45. van der Graaf, A., et al., Dyslipidemia of mothers with familial hypercholesterolemia deteriorates lipids in adult offspring. Arterioscler Thromb Vasc Biol, 2010. 30(12): p. 2673-7. 46. Napoli, C., et al., Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet, 1999. 354(9186): p. 1234-41. 47. Mendelson, M.M., et al., Association of Maternal Prepregnancy Dyslipidemia With Adult Offspring Dyslipidemia in Excess of Anthropometric, Lifestyle, and Genetic Factors in the Framingham Heart Study. JAMA Cardiol, 2016. 1(1): p. 26-35. 48. Versmissen, J., et al., Maternal inheritance of familial hypercholesterolemia caused by the V408M low-density lipoprotein receptor mutation increases mortality. Atherosclerosis, 2011. 219(2): p. 690-3. 49. Gårdebjer, E.M., et al., Maternal alcohol intake around the time of conception causes glucose intolerance and insulin insensitivity in rat offspring, which is exacerbated by a postnatal high-fat diet. Faseb j, 2015. 29(7): p. 2690-701. 50. Küpers, L.K., et al., Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight. Nat Commun, 2019. 10(1): p. 1893. 51. Dor, Y. and H. Cedar, Principles of DNA methylation and their implications for biology and medicine. Lancet, 2018. 392(10149): p. 777-786. 52. Jones, P.A. and S.M. Taylor, Cellular differentiation, cytidine analogs and DNA methylation. Cell, 1980. 20(1): p. 85-93. 53. Christman, J.K., et al., Effect of 5-azacytidine on differentiation and DNA methylation in human promyelocytic leukemia cells (HL-60). Cancer Res, 1983. 43(2): p. 763-9. 54. Creusot, F., G. Acs, and J.K. Christman, Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2''-deoxycytidine. J Biol Chem, 1982. 257(4): p. 2041-8. 55. Taylor, S.M. and P.A. Jones, Mechanism of action of eukaryotic DNA methyltransferase. Use of 5-azacytosine-containing DNA. J Mol Biol, 1982. 162(3): p. 679-92. 56. Christman, J.K., 5-Azacytidine and 5-aza-2''-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene, 2002. 21(35): p. 5483-95. 57. Wilson, V.L., P.A. Jones, and R.L. Momparler, Inhibition of DNA methylation in L1210 leukemic cells by 5-aza-2''-deoxycytidine as a possible mechanism of chemotherapeutic action. Cancer Res, 1983. 43(8): p. 3493-6. 58. Jüttermann, R., E. Li, and R. Jaenisch, Toxicity of 5-aza-2''-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci U S A, 1994. 91(25): p. 11797-801. 59. Karahoca, M. and R.L. Momparler, Pharmacokinetic and pharmacodynamic analysis of 5-aza-2''-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clin Epigenetics, 2013. 5(1): p. 3. 60. Zhou, L., et al., Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases. J Mol Biol, 2002. 321(4): p. 591-9. 61. Momparler, R.L., Pharmacology of 5-Aza-2''-deoxycytidine (decitabine). Semin Hematol, 2005. 42(3 Suppl 2): p. S9-16. 62. Liu, K., et al., Endogenous assays of DNA methyltransferases: Evidence for differential activities of DNMT1, DNMT2, and DNMT3 in mammalian cells in vivo. Mol Cell Biol, 2003. 23(8): p. 2709-19. 63. Cao, Q., et al., Inhibiting DNA Methylation by 5-Aza-2''-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. Endocrinology, 2014. 155(12): p. 4925-38. 64. Liu, Y., et al., DNA hypermethylation: A novel mechanism of CREG gene suppression and atherosclerogenic endothelial dysfunction. Redox Biol, 2020. 32: p. 101444. 65. Dunn, J., et al., Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J Clin Invest, 2014. 124(7): p. 3187-99. 66. Papandreou, I., et al., HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab, 2006. 3(3): p. 187-97. 67. Suzuki, N. and M. Yamamoto, Roles of renal erythropoietin-producing (REP) cells in the maintenance of systemic oxygen homeostasis. Pflugers Arch, 2016. 468(1): p. 3-12. 68. Dai, Y., et al., HIF-1alpha induced-VEGF overexpression in bone marrow stem cells protects cardiomyocytes against ischemia. J Mol Cell Cardiol, 2007. 42(6): p. 1036-44. 69. Metallo, C.M., et al., Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature, 2011. 481(7381): p. 380-4. 70. Fukuda, R., et al., HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell, 2007. 129(1): p. 111-22. 71. Min, I.M., et al., The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell, 2008. 2(4): p. 380-91. 72. Wang, Z., et al., Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement. Blood, 2009. 113(20): p. 4856-65. 73. Flamme, I., T. Frölich, and W. Risau, Molecular mechanisms of vasculogenesis and embryonic angiogenesis. J Cell Physiol, 1997. 173(2): p. 206-10. 74. Jain, S., et al., Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev, 1998. 73(1): p. 117-23. 75. Wiesener, M.S., et al., Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. Faseb j, 2003. 17(2): p. 271-3. 76. Compernolle, V., et al., Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med, 2002. 8(7): p. 702-10. 77. Tian, H., et al., The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev, 1998. 12(21): p. 3320-4. 78. Scortegagna, M., et al., Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-/- mice. Nat Genet, 2003. 35(4): p. 331-40. 79. Peng, J., et al., The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci U S A, 2000. 97(15): p. 8386-91. 80. Mastrogiannaki, M., et al., HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J Clin Invest, 2009. 119(5): p. 1159-66. 81. Shah, Y.M., et al., Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab, 2009. 9(2): p. 152-64. 82. Morita, M., et al., HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. Embo j, 2003. 22(5): p. 1134-46. 83. Gruber, M., et al., Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A, 2007. 104(7): p. 2301-6. 84. Rankin, E.B., et al., Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest, 2007. 117(4): p. 1068-77. 85. Scortegagna, M., et al., HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner. Blood, 2005. 105(8): p. 3133-40. 86. Downes, N.L., et al., Differential but Complementary HIF1α and HIF2α Transcriptional Regulation. Mol Ther, 2018. 26(7): p. 1735-1745. 87. Raval, R.R., et al., Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol, 2005. 25(13): p. 5675-86. 88. Takeda, N., et al., Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev, 2010. 24(5): p. 491-501. 89. Matak, P., et al., Myeloid HIF-1 is protective in Helicobacter pylori-mediated gastritis. J Immunol, 2015. 194(7): p. 3259-66. 90. Choe, S.S., et al., Macrophage HIF-2α ameliorates adipose tissue inflammation and insulin resistance in obesity. Diabetes, 2014. 63(10): p. 3359-71. 91. Kobayashi, H., et al., Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. J Immunol, 2012. 188(10): p. 5106-15. 92. Reeves, P.G., F.H. Nielsen, and G.C. Fahey, Jr., AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr, 1993. 123(11): p. 1939-51. 93. Wang, F., et al., Glycolytic Stimulation Is Not a Requirement for M2 Macrophage Differentiation. Cell Metab, 2018. 28(3): p. 463-475.e4. 94. Divakaruni, A.S., et al., Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis. Cell Metab, 2018. 28(3): p. 490-503.e7. 95. Yabushita, T., et al., Mitotic perturbation is a key mechanism of action of decitabine in myeloid tumor treatment. Cell Rep, 2023. 42(9): p. 113098. 96. 李依靜, ApoE 基因缺乏母鼠施打 DNA 甲基轉移酶抑制劑對子代小鼠動脈粥狀硬化進程之影響：巨噬細胞極化分化之角色, in 分子與細胞生物學研究所. 2020, 國立臺灣大學: 台北市. p. 182. 97. Chen, Y.S., et al., Inhibiting DNA methylation switches adipogenesis to osteoblastogenesis by activating Wnt10a. Sci Rep, 2016. 6: p. 25283. 98. Liang, J., et al., 5-Aza-2''-Deoxycytidine Regulates White Adipocyte Browning by Modulating miRNA-133a/Prdm16. Metabolites, 2022. 12(11). 99. Wang, X., et al., Epigenetic regulation of macrophage polarization and inflammation by DNA methylation in obesity. JCI Insight, 2016. 1(19): p. e87748. 100. Liu, Z.H., et al., Methylation status of CpG sites in the MCP-1 promoter is correlated to serum MCP-1 in Type 2 diabetes. J Endocrinol Invest, 2012. 35(6): p. 585-9. 101. Chen, Y.T., et al., Inhibition of DNA methyltransferase 1 increases nuclear receptor subfamily 4 group A member 1 expression and decreases blood glucose in type 2 diabetes. Oncotarget, 2016. 7(26): p. 39162-39170. 102. Hodgin, J.B. and N. Maeda, Minireview: estrogen and mouse models of atherosclerosis. Endocrinology, 2002. 143(12): p. 4495-501. 103. Marsh, M.M., et al., Protection against atherosclerosis by estrogen is independent of plasma cholesterol levels in LDL receptor-deficient mice. J Lipid Res, 1999. 40(5): p. 893-900. 104. Elhage, R., et al., 17 beta-estradiol prevents fatty streak formation in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol, 1997. 17(11): p. 2679-84. 105. Bourassa, P.A., et al., Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A, 1996. 93(19): p. 10022-7. 106. Freedman, D.S., et al., Sex and age differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy: the Framingham Study. Clin Chem, 2004. 50(7): p. 1189-200. 107. Wang, X., F. Magkos, and B. Mittendorfer, Sex differences in lipid and lipoprotein metabolism: it''s not just about sex hormones. J Clin Endocrinol Metab, 2011. 96(4): p. 885-93. 108. Schubert, C.M., et al., Lipids, lipoproteins, lifestyle, adiposity and fat-free mass during middle age: the Fels Longitudinal Study. Int J Obes (Lond), 2006. 30(2): p. 251-60. 109. AlSiraj, Y., et al., XX sex chromosome complement promotes atherosclerosis in mice. Nat Commun, 2019. 10(1): p. 2631. 110. Bouchareychas, L., et al., Macrophage Exosomes Resolve Atherosclerosis by Regulating Hematopoiesis and Inflammation via MicroRNA Cargo. Cell Rep, 2020. 32(2): p. 107881. 111. Kiouptsi, K., et al., Germ-free housing conditions do not affect aortic root and aortic arch lesion size of late atherosclerotic low-density lipoprotein receptor-deficient mice. Gut Microbes, 2020. 11(6): p. 1809-1823. 112. Ouimet, M., et al., MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest, 2015. 125(12): p. 4334-48. 113. Vats, D., et al., Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab, 2006. 4(1): p. 13-24. 114. Rodríguez-Prados, J.C., et al., Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol, 2010. 185(1): p. 605-14. 115. Freemerman, A.J., et al., Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem, 2014. 289(11): p. 7884-96. 116. Tannahill, G.M., et al., Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature, 2013. 496(7444): p. 238-42. 117. Huang, S.C., et al., Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol, 2014. 15(9): p. 846-55. 118. Qiao, G., et al., Enolase 1, a Moonlighting Protein, as a Potential Target for Cancer Treatment. Int J Biol Sci, 2021. 17(14): p. 3981-3992. 119. Fang, H.Y., et al., Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood, 2009. 114(4): p. 844-59. 120. Imtiyaz, H.Z., et al., Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest, 2010. 120(8): p. 2699-714. 121. Susen, R.M., et al., Macrophage HIF-2α regulates tumor-suppressive Spint1 in the tumor microenvironment. Mol Carcinog, 2019. 58(11): p. 2127-2138. 122. Gardiner-Garden, M. and M. Frommer, CpG islands in vertebrate genomes. J Mol Biol, 1987. 196(2): p. 261-82. 123. Eckhardt, F., et al., DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet, 2006. 38(12): p. 1378-85. 124. Dahlet, T., et al., Genome-wide analysis in the mouse embryo reveals the importance of DNA methylation for transcription integrity. Nat Commun, 2020. 11(1): p. 3153. 125. Bakshi, C., R. Vijayvergiya, and V. Dhawan, Aberrant DNA methylation of M1-macrophage genes in coronary artery disease. Scientific Reports, 2019. 9. 126. Rawłuszko-Wieczorek, A.A., et al., Prognostic potential of DNA methylation and transcript levels of HIF1A and EPAS1 in colorectal cancer. Mol Cancer Res, 2014. 12(8): p. 1112-27. 127. Westerlund, I., et al., Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression. Proc Natl Acad Sci U S A, 2017. 114(30): p. E6137-e6146. 128. Thienpont, B., et al., Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature, 2016. 537(7618): p. 63-68. 129. Fischer, A.P. and S.L. Miles, Silencing HIF-1α induces TET2 expression and augments ascorbic acid induced 5-hydroxymethylation of DNA in human metastatic melanoma cells. Biochem Biophys Res Commun, 2017. 490(2): p. 176-181. 130. Mariani, C.J., et al., TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma. Cell Rep, 2014. 7(5): p. 1343-1352. 131. Laukka, T., et al., Fumarate and Succinate Regulate Expression of Hypoxia-inducible Genes via TET Enzymes. J Biol Chem, 2016. 291(8): p. 4256-65. 132. Lin, G., et al., Hypoxia induces the expression of TET enzymes in HepG2 cells. Oncol Lett, 2017. 14(6): p. 6457-6462. 133. Xu, X.H., et al., Hypoxic-stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non-small cell lung cancer. Faseb j, 2018: p. fj201700715. 134. Lachance, G., et al., DNMT3a epigenetic program regulates the HIF-2α oxygen-sensing pathway and the cellular response to hypoxia. Proc Natl Acad Sci U S A, 2014. 111(21): p. 7783-8. 135. D''Anna, F., et al., DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance. Genome Biol, 2020. 21(1): p. 182. 136. Humphries, S., et al., Crosstalk between DNA methylation and hypoxia in acute myeloid leukaemia. Clin Epigenetics, 2023. 15(1): p. 150. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/92047 | - |
| dc.description.abstract | 動脈粥狀硬化形成的過程，巨噬細胞會吞噬血液中過多的氧化態低密度脂蛋白（Oxidized low-density lipoproteins, ox-LDL），形成泡沫細胞堆積在血管內層，進而形成纖維性斑塊。已知母鼠高膽固醇血症能透過表觀遺傳的方式使胎兒罹患動脈粥狀硬化的機會增加。初步研究已發現降低親代母鼠DNA甲基化程度可以改善子代雄鼠動脈粥狀硬化的程度，可能和促發炎M1巨噬細胞數量的減少、抑制發炎M2巨噬細胞數量的增加有關，但是對於表觀遺傳和巨噬細胞之間的關係仍不清楚。因此本實驗欲探討親代營養狀況如何透過表觀遺傳的調控影響子代巨噬細胞極化的分子機制。以ApoE－/－小鼠作為動物模型，在孕前、哺乳期間給予DNA甲基轉移酶抑制劑5-Aza-2‘-deoxycytidine（5-aza-dC），子代離乳後皆餵食西方飲食。首先，主動脈RNA定序結果顯示親代母鼠經過5-aza-dC處理後雄性子代主動脈差異表現基因（differentially expressed genes, DEG）與巨噬細胞極化相關路徑高度相關，接著利用從骨髓衍生的巨噬細胞（bone marrow-derived macrophage, BMDM），我們確認了親代母鼠經過5-aza-dC處理可以降低雄性子代BMDM誘導成M1巨噬細胞數量，功能性分析上發現M1巨噬細胞糖解能力下降，M2巨噬細胞氧化磷酸化能力增加，之後，為了進一步探討分子機制，我們利用BMDM進行RNA定序，透過Gene Ontology（GO）分析得知DEG與細胞週期、轉錄因子結合及轉錄調控等生物路徑高度相關，並且我們發現親代母鼠經過5-aza-dC處理後雄性子代巨噬細胞中轉錄因子HIF2α表現量增加，最後，在Raw264.7細胞過度表現Hif2a，證明部分M2巨噬細胞相關基因表現量上升，表示高表現HIF2α可能促進巨噬細胞傾向往M2極化，然而，我們在BMDM中Hif2a啟動子的特定序列上並未觀察到DNA甲基化有明顯改變的情形。綜合以上結果，我們發現親代母鼠孕前及哺乳期間給予5-aza-dC使雄性子代巨噬細胞Hif2a表現量增加，可能將巨噬細胞趨勢M2極化，進而改善子代雄鼠動脈粥狀硬化。 | zh_TW |
| dc.description.abstract | During the development of atherosclerosis, macrophages uptake excessive oxidized low-density lipoproteins (ox-LDL) and transform into foam cells. The accumulation of foam cells in the arterial intima leads to the formation of fibrous plaques. Our previous study shows that maternal hypercholesterolemia increases the risk of developing atherosclerosis in adult offspring, potentially through epigenetic mechanism. Furthermore, our preliminary results indicate that reducing DNA methylation levels in dams attenuates atherosclerosis development in male offspring, which may be associated with a reduction in M1 macrophages and an increase in M2 macrophages. However, the relationship between epigenetic inheritance and macrophages remains unclear. Here, we aim to investigate the molecular mechanism of maternal effect in macrophages polarization through epigenetic regulation. In this study, DNA methyltransferase inhibitor, 5-Aza-2'-deoxycytidine (5-aza-dC), was given to ApoE－/－ female mice before pregnancy and during lactation. First, RNA-sequence data obtained from the aorta in male offspring derived from 5-aza-dC-treated dams exhibited a high correlation with pathways related to macrophage polarization. Subsequently, we used bone marrow-derived macrophage (BMDM) and confirmed that maternal 5-aza-dC treatment reduced the cell populations of M1 macrophages in male offspring. For functional analysis, the glycolytic capacity of M1 macrophages decreased and the oxidative phosphorylation capacity of M2 macrophages increased in male offspring derived from 5-aza-dC-treated dams. Moreover, we analyzed RNA-sequence data obtained from BMDM using Gene Ontology (GO) enrichment analysis. We identified differentially expressed genes were highly enriched in pathways associated with cell cycle, transcription factor binding and positive regulation of transcription. We specifically focused on transcription factor HIF2α, which is implicated in macrophage polarization and was upregulated in the macrophages isolated from male offspring derived from 5-aza-dC-treated dams. In particular, we overexpressed HIF2α in Raw264.7 cells and observed an increase in the expression of genes related to M2 macrophages. However, the DNA methylation level of the specific region within HIF2α promoter was unaltered in the macrophages isolated from male offspring derived from 5-aza-dC-treated dams compared to those isolated from male offspring derived from PBS-treated dams. In summary, our findings suggest that maternal 5-aza-dC treatment before pregnancy and during lactation can increase the expression of HIF2α in the macrophages from male offspring and potentially drive macrophage polarization toward M2 macrophages. This, in turn, partially ameliorates atherosclerosis development in male offspring mice. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-03-04T16:16:18Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-03-04T16:16:18Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 謝辭 I
摘要 II Abstract III 目次 V 圖次 VIII 表次 X 縮寫表 XII 第一章 緒論 1 第一節 前言 1 第二節 文獻回顧 3 一、動脈粥狀硬化 3 二、Apolipoprotein E缺乏（ApoE－/－）老鼠 9 三、胎兒規劃（Fetal programming） 10 四、表觀遺傳 11 五、5-Aza-2’-deoxycytidine（5-aza-dC） 12 六、Hypoxia-inducible factor 13 第三節 研究動機 15 第二章 材料與方法 16 第一節 實驗設計 16 第二節 動物實驗 17 一、實驗老鼠品系 17 二、飼料配製 17 三、基因型鑑定（Genotyping） 19 四、老鼠血液收集及犧牲方式 20 五、血液生化指標分析 21 六、主動脈竇冷凍切片進行油紅染色分析 22 第三節 初代細胞實驗 24 一、骨髓分離巨噬細胞（Bone marrow-derived macrophage, BMDM） 24 二、測定巨噬細胞基因表現 25 三、流式細胞儀分析M1、M2巨噬細胞極化潛力 28 四、巨噬細胞產酸率及氧氣消耗率率測定 31 五、次世代定序 32 六、DNA甲基化分析 33 第四節 細胞實驗 38 一、培養L929細胞株 38 二、培養Raw264.7細胞株 38 三、過度表現Hif2a於Raw264.7細胞株 38 四、統計分析 40 第五節 藥品及培養基配製 41 一、藥品配製 41 二、培養基配製 42 第三章 實驗結果 44 一、5-aza-dC對於親代母鼠的表徵影響 44 二、親代母鼠施打5-aza-dC對於子代小鼠的表徵影響 45 三、親代母鼠施打5-aza-dC對於子代雄鼠巨噬細胞極化之影響 47 四、親代母鼠施打5-aza-dC對於子代雄鼠巨噬細胞極化之分子機制 51 五、Raw264.7細胞過度表現Hif2a對於巨噬細胞極化之影響 53 六、子代雄鼠巨噬細胞Hif2a CpG islands甲基化程度 54 第四章 討論與結論 83 第一節 討論 83 一、5-aza-dC對於親代母鼠的表徵影響 83 二、親代母鼠施打5-aza-dC對於子代小鼠的表徵影響 83 三、動脈粥狀硬化的性別差異 84 四、子代主動脈竇斑塊面積不受5-aza-dC影響 85 五、親代母鼠施打5-aza-dC對於子代雄鼠巨噬細胞極化之影響 85 六、轉錄因子文獻回顧 87 七、Raw264.7細胞過度表現Hif2a使部分M1、M2標記基因表現上升 87 八、子代雄鼠巨噬細胞Hif2a CpG islands無甲基化 88 九、缺氧和DNA甲基化的關係 91 第二節 總討論 92 第三節 結論 95 第五章 附錄 96 第六章 參考文獻 100 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 表觀遺傳 | zh_TW |
| dc.subject | 動脈粥狀硬化 | zh_TW |
| dc.subject | HIF2α | zh_TW |
| dc.subject | 巨噬細胞極化 | zh_TW |
| dc.subject | DNA甲基化 | zh_TW |
| dc.subject | atherosclerosis | en |
| dc.subject | DNA methylation | en |
| dc.subject | HIF2α | en |
| dc.subject | macrophage polarization | en |
| dc.subject | epigenetics | en |
| dc.title | 探討動脈粥狀硬化中發育程序化影響巨噬細胞極化之分子機制 | zh_TW |
| dc.title | Exploring the mechanism of fetal programming on macrophage polarization in atherosclerosis | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 黃青真;蘇慧敏;林建達 | zh_TW |
| dc.contributor.oralexamcommittee | Ching-Jang Huang;Hui-Min Su;Jian-Da Lin | en |
| dc.subject.keyword | 動脈粥狀硬化,表觀遺傳,DNA甲基化,巨噬細胞極化,HIF2α, | zh_TW |
| dc.subject.keyword | atherosclerosis,epigenetics,DNA methylation,macrophage polarization,HIF2α, | en |
| dc.relation.page | 110 | - |
| dc.identifier.doi | 10.6342/NTU202400528 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2024-02-11 | - |
| dc.contributor.author-college | 生命科學院 | - |
| dc.contributor.author-dept | 生化科技學系 | - |
| dc.date.embargo-lift | 2029-02-01 | - |
| 顯示於系所單位： | 生化科技學系 | |
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