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論文中文名稱:藉由藥效基團模型、虛擬篩選、分子嵌合及分子動態模擬來搜尋新型的抗動脈粥狀硬化症化合物 [以論文名稱查詢館藏系統]
論文英文名稱:Discovery of novel anti-atherosclerotic compounds by pharmacophore modeling, virtual screening, molecular docking and molecular dynamics simulations. [以論文名稱查詢館藏系統]
院校名稱:臺北科技大學
學院名稱:工程學院
系所名稱:生物科技研究所
畢業學年度:100
出版年度:101
中文姓名:陳沐家
英文姓名:Mu-Jia Chen
研究生學號:99688021
學位類別:碩士
語文別:英文
口試日期:2012-07-20
論文頁數:122
指導教授中文名:劉宣良
指導教授英文名:Hsuan-Liang Liu
口試委員中文名:蔡偉博;何意;黃志宏
口試委員英文名:Wei-Bor Tsai;Yih Ho;Chih-Hung Huang
中文關鍵詞:動脈粥狀硬化症醯基-輔酶A:膽固醇醯基轉移酶膽固醇酯轉移蛋白藥效基團虛擬篩選分子嵌合分子動態模擬
英文關鍵詞:AtherosclerosisAcyl-coenzyme A: cholesterol acyltransferase (ACAT)Cholesteryl ester transfer protein (CETP)pharmacophorevirtual screeningmolecular dockingmolecular dynamic
論文中文摘要:動脈粥狀硬化症是由於長時間的脂質與膽固醇堆積於動脈血管壁中,其產生的硬塊使血管變得狹窄,而導致心血管疾病的發生。過去的文獻指出,已有大量的抗動脈粥狀硬化症藥物被開發,然而,其藥物卻有多種的副作用出現在人類及動物的活體實驗中。至今,尚缺乏一個有效且不具副作用的抗動脈粥狀硬化症藥物,為了尋找更有效更低副作用的藥物,我們採用多種電腦輔助藥物設計原件包含了藥效基團、虛擬篩選、分子嵌合與分子動態模擬來進行本次實驗。在先前的研究指出,醯基-輔酶A:膽固醇醯基轉移酶與膽固醇酯轉移蛋白對於動脈粥狀硬化症皆扮演重要角色。醯基-輔酶A:膽固醇醯基轉移酶存在兩種相似的型態,故我們分別針對第一型與第二型醯基-輔酶A:膽固醇醯基轉移酶架設以配體為基礎的HipHopRefine與HypoRefine的藥效基團模型,並在經過Güner–Henry (GH) 評分方法驗證後都顯示兩者皆具有好的預測能力,接著我們結合這兩種模型並以虛擬篩選模組進行ZINC化學資料庫之篩選,而最後十個化合物對於這兩者藥效基團具有高吻合度並有多樣化骨幹結構將作為未來藥物開發上可能的前導藥物。另一方面,我們以一系列膽固醇酯轉移蛋白的抑制劑來架構HipHop藥效基團模型,而其中最好的模型(HipHop-1)具有最高的GH評分分數,故我們以此模型套用到NCI及Maybridge化學資料庫的虛擬藥物篩選,再經由分子嵌合及分子動力模擬的方法來篩選出四個最具好結合力的化合物。而本實驗所挑選出來的化合物可應用於日後設計新型並更具活性的抗動脈粥狀硬化症用藥來達到臨床上的應用。
論文英文摘要:Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and fibrous elements in the large arteries; moreover, it is the primary cause of cardiovascular diseases. In previous studies, a great number of anti-atherosclerotic drugs have been developed but several side effects were found in animal and human studies. Until recently, an effective anti-atherosclerotic drug without side effects has not been discovered. Therefore, we applied many computational approaches including pharmacophore modeling, virtual screening, molecular docking and molecular dynamic for searching more effective and less side effects anti-atherosclerotic drugs. Furthermore, it was found that there are two predominant targets for anti-atherosclerotic: Acyl-coenzyme A: cholesterol acyltransferase (ACAT) and Cholesteryl ester transfer protein (CETP). For ACAT, there are two similar types ACAT-1 and ACAT-2, and then we constructed ligand-base pharmacophore models: HipHopRefine and HypoRefine for ACAT-1 and ACAT-2 respectively. After Güner–Henry (GH) scoring methods validation, both of HipHopRefine and HypoRefine show good predictive ability. Subsequently, we utilized two pharmacophore models to screen ZINC database for obtaining more potential dual ACAT inhibitors. After virtual screening, 10 hits with high pharmacophore fitvalue and diverse scaffolds were identified as potential lead compounds. As to CETP, we also constructed HipHop pharmacophore model by a series of CETP inhibitors to search another potential drugs of atherosclerosis. The best model HipHop-1 was further validated by GH scoring methods and applied to screen the NCI and Maybridge databases. Then, molecular docking and molecular dynamic were conducted to retrieve 4 potential compounds. In summary, the results of this study can be applied to the design of new and more potent anti-atherosclerotic drugs for clinical purposes.
論文目次:ABSTRACT i
ACKNOWLEDGEMENT v
CONTENTS vi
TABLE CONTENTS ix
FIGURE CONTENTS xi
Chapter 1 GENERAL INTRODUCTION 1
Chapter 2 LITERATURE REVIEW 3
2.1 Atherosclerosis 3
2.1.1 The pathophysiology of atherosclerosis 4
2.1.2 The development of anti-atheroscelrotic drugs 10
2.2 Acyl-coenzyme A: cholesterol acyltransferase (ACAT) 13
2.2.1 Tissue distribution of ACAT-1 and ACAT-2 14
2.2.2 Regulation of ACAT-1 and ACAT-2 15
2.2.3 Previous study of ACAT inhibitors 17
2.3 Cholesteryl ester transfer protein (CETP) 19
2.3.1 The relationship between CETP and Atherosclerosis 21
2.3.2 Previous study of CETP inhibitors 23
Chapter 3 MOLECULAR MODELING 25
3.1 Overview 25
3.2 Pharmacophore modeling 26
3.2.1 HipHop pharmacophore 28
3.2.2 Hypogen pharmacophore 29
3.3 Virtual screening 29
3.4 Molecular docking 30
3.4.1 Docking programs 31
3.4.1.1 CDOCKER algorithm 31
3.4.1.2 DOCK algorithm 33
3.4.1.3 FlexX algorithm 33
3.4.1.4 GOLD algorithm 34
3.4.1.5 LibDock 35
3.5 Molecular dynamics simulations 36
3.5.1 Force Fields 38
3.5.1.1 Overview Several Classical Force Fields 38
3.5.1.2 The Parameters in the Force Field 39
3.5.1.3 Functional Form of the CHARMm Force Field 43
3.5.2 Minimization 45
3.5.3 Equilibration 48
3.5.4 Molecular Dynamics 49
Chapter 4 Discovery of dual Acyl-coenzyme A: cholesterol acyltransferase inhibitors via pharmacophore modeling and virtual screening 52
4.1 Abstract 52
4.2 Introduction 53
4.3 Materials and Methods 56
4.3.1 Pharmacophore generation 56
4.3.1.1 HipHop pharmacophore model 56
4.3.1.2 Hypogen pharmacophore model 56
4.3.2 Pharmacophore models validation 58
4.3.2.1 HipHop pharmacophore model validation 58
4.3.2.2 Hypogen pharmacophore model validation 59
4.3.3 Pharmacophore model with excluded volumes 59
4.3.4 2D finger print similarity search 60
4.3.5 Virtual screening 60
4.4 Results and discussion 62
4.4.1 HipHop pharmacophore model of ACAT-1 62
4.4.2 Validation of HipHop-1 model 65
4.4.3 Hypogen pharmacophore model of ACAT-2 65
4.4.4 Validation of Hypo-1 model 69
4.4.5 Pharmacophore model with excluded volumes 72
4.4.6 Pharmacophore-based virtual screening 74
4.5 Conclusions 79
4.6 References 79
Chapter 5 Identification of novel potential CETP inhibitor by pharmacophore modeling, virtual screening, molecular docking, and molecular dynamics simulation approaches 87
5.1 Abstract 87
5.2 Introduction 88
5.3 Materials and Methods 90
5.3.1 Data set preparation 90
5.3.2 HipHop pharmacophore generation and validation 91
5.3.3 Virtual sceening 92
5.3.4 Molecular docking 93
5.3.5 Molecular dynamic simulation 94
5.4 Results and discussion 95
5.4.1 Pharmacophore modeling of CETP 95
5.4.2 Virtual screening 98
5.4.3 Docking analysis 99
5.4.4 Virtual screening 99
5.4.5 Molecular dynamic simulation analysis 103
5.5 Conclusions 107
5.6 References 107
Chapter 6 GENERAL CONCLUSIONS 111
Chapter 7 GENERAL REFERENCES 113
論文參考文獻:Agellon LB, Quinet EM, Gillette TG, Drayna DT, Brown ML, Tall AR (1990) Organization of the human cholesteryl ester transfer protein gene. Biochemistry 29(6):1372–1376
Aragane K, Kojima K, Fujinami K, Kamei J and Kusunoki J (2001) Effect of F-1394, an acyl-CoA:cholesterol acyltransferase inhibitor, on atherosclerosis induced by high cholesterol diet in rabbits. Atherosclerosis 158, 139-145.
Aragane K, Fujinami K, Kojima K and Kusunoki J (2001) ACAT inhibitor F-1394 prevents intimal hyperplasia induced by balloon injury in rabbits. J. Lipid. Res. 42, 480-488.
Asami Y, Yamagishi I, Murakami S, Araki H., Tsuchida K and Higuchi S (1998) HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol- fed rabbits. Life. Sci. 62, 1055-1063.
Barter PJ, Caulfield M., Eriksson M., Grundy SM., Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR and Tall AR, Brewer B; ILLUMINATE Investigators (2007) Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122.
Berti JA, de Faria EC and Oliveira HC (2005) Atherosclerosis in aged mice over-expressing the reverse cholesterol transport genes. Braz. J. Med. Biol. Res. 38, 391–398.
Bocan TM, Mueller SB, Uhlendorf PD, Newton RS and Krause BR (1991) Comparison of CI-976, an ACAT inhibitor, and selected lipid-lowering agents for antiatherosclerotic activity in iliac-femoral and thoracic aortic lesions. A biochemical, morphological, and morphometric evaluation. Arterioscler. Thromb. 11, 1830-1843.
Bocan TM, Krause BR, Rosebury WS, Mueller SB, Lu X, Dagle C, Major T, Lathia C and Lee H (2000) The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits. Arterioscler. Thromb. Vasc. Biol. 20, 70-79.
Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G (2007) PPAR? activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 6, 137–143.
Bruce C, Beamer LJ, Tall AR (1998) The implications of the structure of the bactericidal/permeability increasing protein on the lipid-transfer function of the cholesteryl ester transfer protein. Curr Opin Struct Biol 8:426–434
Casquero AC, Berti JA, Salerno AG, Bighetti EJ, Cazita PM, Ketelhuth DF, Gidlund M and Oliveira HC (2006) Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice. J. Lipid Res. 47, 1526–1534.
Cazita PM, Berti JA, Aoki C, Gidlund M, Harada LM, Nunes VS, Quintao EC, Oliveira HC (2003) Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice. J. Lipid Res. 44, 33–40.
Chang CC, Huh HY, Cadigan KM and Chang TY (1993) Molecular cloning and functional expression of human acylcoenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J. Biol. Chem. 268, 20747-20755.
Chang TY, Chang CC and Cheng D (1997) Acyl-coenzyme A:cholesterol acyltransferase. Annu. Rev. Biochem. 66, 613-638.
Chang CC, Sakashita N, Ornvold K, Lee O, Chang ET, Dong R, Lin S, Lee CY, Strom SC, Kashyap R, Fung JJ, Farese RV. Jr, Patoiseau JF, Delhon A and Chang TY (2000) Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and small intestine. J. Biol. Chem. 275, 28083-28092.
Chang TY, Chang CC, Lin S, Yu C, Li BL and Miyazaki A (2001) Roles of acyl-coenzyme A:cholesterol acyltransferase-1 and -2. Curr. Opin. Lipidol. 12, 289- 296.
Cheng W, Kvilekval KV and Abumrad NA (1995) Dexamethasone enhances accumulation of cholesteryl esters by human macrophages. Am. J. Physiol. 269, E642-648.
Delsing DJ, Offerman EH, van Duyvenvoorde W, van Der Boom H, de Wit EC, Gijbels MJ, van Der Laarse A, Jukema JW, Havekes LM and Princen HM (2001) Acyl-CoA:cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-Leiden mice. Circulation 103, 1778-1786.
Drayna D, Jarnagin AS, McLean J, Henzel W, Koehr W, Fielding C, Lawn R (1987) Cloning and sequencing of human cholestryl ester transfer protein cDNA. Nature 327(61234):632–634
Duriez P, Bordet R. and Berthelot P (2007) The strange case of Dr HDL and Mr HDL: does a NO’s story illuminate the mystery of HDL’s dark side uncovered
Föger B, Chase M, Amar MJ, Vaisman BL, Shamburek RD, Paigen B, Fruchart-Najib J, Paiz JA, Koch CA, Hoyt RF, Brewer HB. Jr and Santamarina-Fojo S (1999) Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J. Biol. Chem. 274, 36912–36920.
Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, Hershey J C, Keller WJ, Ma X, McPherson HE, Messina E, Peterson LB, Sharif-Rodriguez W, Siegl PK, Sinclair PJ, Sparrow CP, Stevenson AS, Sun SY, Tsai C, Vargas H., Walker M 3rd, West SH., White V and Woltmann RF (2008) Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br. J. Pharmacol. 154, 1465–1473.
Furukawa K, Hori M, Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Miyazaki A, Nakayama H and Horiuchi S (2004) Adiponectin down-regulates acyl- coenzyme A:cholesterol acyltransferase-1 in cultured human monocyte-derived
macrophages. Biochem. Biophys. Res. Commun. 317, 831-836.
Glomset JA (1968) The plasma lecithins: cholesterol acyltransferase reaction. J. Lipid Res. 9, 155–167.
Gimbrone MA, Jr, Topper JN, Nagel T, Anderson KR. and Garcia-Cardeña G (2000) Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann. NY Acad. Sci. 902, 230–240.
Goldbourt U and Neufeld HN (1988) Genetic aspects of arteriosclerosis Arteriosclerosis 6, 357–377.
Gue´rin M, Dolphin PJ, Chapman MJ (1994) Preferential cholesteryl ester acceptors among the LDL subspecies of subjects with familial hypercholesterolemia. Arterioscler Thromb 14:679–685
Harder C, Lau P, Meng A, Whitman SC and McPherson R (2007) Cholesteryl ester transfer protein (CETP) expression protects against diet induced atherosclerosis in SR-BI deficient mice. Arterioscler. Thromb. Vasc. Biol. 27, 858–864.
Hayek T, Masucci-Magoulas L, Jiang X, Walsh A, Rubin E, Breslow JL and Tall AR (1995) Decreased early atherosclerotic lesions in hyper- triglyceridemic mice expressing cholesteryl ester transfer protein transgene. J. Clin. Invest. 96, 2071–2074.
Herrera VL, Makrides SC, Xie HX, Adari H, Krauss RM, Ryan US and Ruiz-Opazo N (1999) Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl saltsensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nat. Med. 5, 1383–1389.
Hofmann K (2000) A superfamily of membrane-bound O-acyltransferases with implications for Wnt signaling. Trends Biochem Sci 25: 111–112.
Hori M, Miyazaki A, Tamagawa H, Satoh M, Furukawa K, Hakamata H, Sasaki Y and Horiuchi S (2004) Up-regulation of acylcoenzyme A:cholesterol acyltransferase-1 by transforming growth factor-beta1 during differentiation of human monocytes into macrophages. Biochem. Biophys. Res. Commun. 320, 501-505.
Ishi M, Tomono Y, Sanma H, Yamoto C, Sekino H, Nomura M and Nakaya N (1994) Pharmacokinetics of novel ACAT inhibitor E5324, in healthy volunteers. Atherosclerosis 109: 283 (253-Abs).
Kako Y, Masse’ M, Huang LS, Tall AR and Goldberg IJ (2002) Lipoprotein lipase deficiency and CETP in streptozotocin-treated apoB-expressing mice. J. Lipid Res. 43, 872–877.
Kataoka K, Shiota T, Takeyasu T, Mochizuki T, Taneda K, Ota M, Tanabe H and Yamaguchi H (1995) Potent inhibitors of acyl-CoA:cholesterol acyltransferase. Structure-activity relationships of novel N-(4-oxochroman-8-yl) amides. J Med Chem 38(16): 3174-86.
Kawano K, Qin SC, Lin M, Tall AR, Jiang XC (2000) Cholesteryl ester transfer protein and phospholipid transfer protein have nonoverlapping functions in vivo. J Biol Chem 275:29477–29481
Kusunoki J, Hansoty DK, Aragane K, Fallon JT, Badimon JJ and Fisher EA (2001) Acyl-CoA:cholesterol acyltransferase inhibition reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 103, 2604-2609.
Libby P (2009) Molecular and cellular mechanisms of the thrombotic complication of atherosclerosis. J. Lipid Res. 50, S352–S357.
Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473(7347): 317-25.
Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, et al. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 121(7): 948-54.
Lusis AJ, Weinreb A & Drake T (1998) A. in Textbook of Cardiovascular Medicine (ed. Topol, E. J.) 2389–2413 (Lippincott-Raven, Philadelphia).
MacLean PS, Bower JF, Vadlamudi S, Osborne JN, Bradfield JF, Burden HW, Bensch WH, Kauffman RF and Barakat HA (2003) Cholesteryl ester transfer protein expression prevents dietinduced atherosclerotic lesions in male db/db mice. Arterioscler. Thromb. Vasc. Biol. 23, 1412–1415.
Majesky MW (2007) Developmental basis of vascular smooth muscle diversity. Arterioscler. Thromb. Vasc. Biol. 27, 1248–1258.
Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW and Melchior GW (1993) Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature 364, 73–75.
Matsuo M, Ito F, Konto A, Aketa M, Tomoi M and Shimomura K (1995) Effect of FR145237, a novel ACAT inhibitor, on atherogenesis in cholesterol-fed and WHHL rabbits. Evidence for a direct effect on the arterial wall. Biochim. Biophys. Acta 1259, 254-260.
Matsuo M, Hashimoto M, Suzuki J, Iwanami K, Tomoi M. and Shimomura K (1996) Difference between normal and WHHL rabbits in susceptibility to the adrenal toxicity of an acyl-CoA:cholesterol acyltransferase inhibitor, FR145237. Toxicol Appl Pharmacol 140(2): 387-92.
Maung K, Miyazaki A, Nomiyama H, Chang CC, Chang TY and Horiuchi S (2001) Induction of acyl-coenzyme A:cholesterol acyltransferase-1 by 1,25- dihydroxyvitamin D(3) or 9-cis-retinoic acid in undifferentiated THP-1 cells. J. Lipid. Res. 42, 181-187.
Mehrabian M, Wen PZ, Fisler J, Davis RC and Lusis AJ (1998) Genetic loci controlling body fat, lipoprotein metabolism, and insulin levels in a multifactorial mouse model. J. Clin. Invest. 101, 2485–2496.
Miyazaki A, Sakashita N, Lee O, Takahashi K, Horiuchi S, Hakamata H, Morganelli PM, Chang CC and Chang TY (1998) Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes- macrophages. Arterioscler. Thromb. Vasc. Biol. 18, 1568-1574.
Moore KJ and Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145(3): 341-55.
Nakaya N, Nakamichi N, Sekino H, Nomura M, Ishii M, Tomono Y and Yamato C (1994) Effect of a novel ACAT inhibitor, E5324, on serum lipids and lipoproteins in healthy volunteers. Atherosclerosis 109: 284 (253-Abs).
Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC and Nissen SE (2008) CETP inhibition, HDL raising and progression of coronary atherosclerosis: insights from ILLUSTRATE. Circulation 118, 2506–2514.
Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP and Tuzcu EM; ILLUSTRATE Investigators. (2007) Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356, 1304–1316.
Oelkers P, Behari A, Cromley D, Billheimer JT and Sturley SL (1998) Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes. J. Biol. Chem. 273, 26765-26771.
Panousis CG and Zuckerman SH (2000) Regulation of cholesterol distribution in macrophage-derived foam cells by interferongamma. J. Lipid. Res. 41, 75-83.
Parini P, Rudel LL (2003) Is there a need for cholesteryl ester transfer protein inhibition? Arterioscler Thromb Vasc Biol 23:374–375
Parini P, Davis M, Lada AT, Erickson SK, Wright TL, Gustafsson U, Sahlin S, Einarsson C, Eriksson M, Angelin B, Tomoda H, Omura S, Willingham MC and Rudel LL (2004) ACAT2 is localized to hepatocytes and is the major cholesterol- esterifying enzyme in human liver. Circulation 110, 2017-2023.
Plump AS, Masucci-Magoulas L, Bruce C, Bisgaier CL, Breslow JL and Tall AR (1999) Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler. Thromb. Vasc. Biol. 19, 1105–1110.
Reindel JF, Dominick MA, Bocan TM, Gough AW and McGuire EJ (1994) Toxicologic effects of a novel acyl-CoA:cholesterol acyltransferase inhibitor in cynomolgus monkeys. Toxicol Pathol 22(5): 510-8.
Rudel LL, Lee RG and Cockman TL (2001) Acyl coenzyme A: cholesterol acyltransferase types 1 and 2: structure and function in atherosclerosis. Curr. Opin. Lipidol. 12, 121-127.
Sakashita N, Miyazaki A, Takeya M, Horiuchi S, Chang CC, Chang TY and Takahashi K (2000) Localization of human acylcoenzyme A: cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues. Am. J. Pathol. 156, 227-236.
Sakashita N, Miyazaki A, Chang CC, Chang TY, Kiyota E, Satoh M, Komohara Y, Morganelli PM, Horiuchi S and Takeya M (2003) Acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) is induced in monocyte-derived macrophages: in vivo and in vitro studies. Lab. Invest. 83, 1569-1581.
Seo T, Oelkers PM, Giattina MR, Worgall TS, Sturley SL and Deckelbaum RJ (2001) Differential modulation of ACAT1 and ACAT2 transcription and activity by long chain free fatty acids in cultured cells. Biochemistry 40, 4756-4762.
Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ (2007) Ly-6Chi monocytes dominate hypercholesterolemia- associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205.
Tabas I, Williams KJ and Boren J (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116, 1832–1844.
Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ (2007) Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194.
Tabas I (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nature Rev. Immunol. 10, 36–46.
Tall AR (1993) Plasma cholesteryl ester transfer protein. J Lipid Res 34:1255–1274
Tanaka H, Ohtsuka I, Kogushi M, Kimura T, Fujimori T, Saeki T, Hayashi K, Kobayashi H, Yamada T, Hiyoshi H and et al. (1994) Effect of the acyl-CoA: cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits. Atherosclerosis 107, 187-201.
Virmani R, Burke AP, Kolodgie FD and Farb A (2002) Vulnerable plaque: the pathology of unstable coronary lesions. J. Interv. Cardiol. 15, 439–446.
Wang H, Germain SJ, Benfield PP and Gillies PJ (1996) Gene expression of acyl-coenzyme-A:cholesterol-acyltransferase is upregulated in human monocytes during differentiation and foam cell formation. Arterioscler. Thromb. Vasc. Biol. 16, 809-814.
Yang JB, Duan ZJ, Yao W, Lee O, Yang L, Yang XY, Sun X., Chang CC, Chang TY, and Li BL (2001) Synergistic transcriptional activation of human Acyl-coenzyme A: cholesterol acyltransterase-1 gene by interferon-gamma and all-trans-retinoic acid THP-1 cells. J. Biol. Chem. 276, 20989-20998.
Yuhanna IS, Zhu Y, Cox BE, Hahner LD, Osborne-Lawrence S, Lu P, Marcel YL, Anderson RG, Mendelsohn ME, Hobbs HH and Shaul PW (2001) High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase. Nat. Med.7, 853–857.
Zilversmit DB, Hughes LB, Balmer J (1975) Stimulation of cholesterol ester exchange by lipoprotein-free rabbit plasma. Biochim Biophys Acta 409:393–398
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