漏芦抑制单核细胞源性泡沫细胞形成的机理研究
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摘要
动脉粥样硬化(Atherosclerosis, AS)是心脑血管疾病的主要病理生理基础. 众所周知,
AS 形成与脂质代谢异常有关 ,尤其与氧化型低密度脂蛋白( Oxidized Low Density
Lipoprotein, oxLDL)有关, oxLDL 被巨噬细胞清道夫受体(Scavenger, SR)所识别, 摄取,
且不受细胞内胆固醇的反馈抑制, 结果细胞内脂质大量积聚, 巨噬细胞转变成富含胆固醇酯
的泡沫细胞——AS 形成早期脂肪条纹的主要细胞类型 ;CD36 是 oxLDL 的主要受体,在泡沫
细胞形成过程中, oxLDL 首先作用于 CD36 受体, 然后通过激活核受体使 CD36 表达增加 ,促
进单核细胞分化成巨噬细胞并摄取 oxLDL 形成泡沫细胞; 而活化的巨噬细胞和 oxLDL 又能加
速 AS 的进展. 因此 ,巨噬细胞, oxLDL, CD36 在AS的发生发展中具有重要作用,也一直是
AS 研究的重点.
整体动脉粥样硬化动物模型研究表明,漏芦水提物可使 AS 病变减轻, 对祁州漏芦水煎
剂成分进行分析 ,漏芦含有多种化学成分, 研究者曾从漏芦根和叶中提取了蜕皮甾酮 ,产率
较高 .因此 ,为了深入研究漏芦的抗 AS 的作用机制及发现其可能的有效成分 ,我们在本课
题的前期研究基础上 ,进行了如下的实验研究, 旨在通过分析漏芦血清药及蜕皮甾酮对单核
细胞摄取 oxLDL 和 CD36 表达的影响 ,进一步证明漏芦抗 AS 的可能机制及对蜕皮甾酮做初步
的药效学筛选.
本研究分为三个部分:
实验一 荧光标记法检测 U937 细胞对 oxLDL 的摄取作用
本实验应用异硫氰酸荧光素( fluorescein isocyanate, FITC) 标记 oxLDL, 通过流式细胞
仪检测不同浓度 oxLDL 的作用下 U937 细胞摄取 oxLDL 的量 ,并在显微镜下观察 U937 细胞的
形态学改变和计算活细胞率. 结果发现: 在 10ug/ml 至 80ug/ml 浓度范围内, 随着 oxLDL 浓
度的增加 U937 细胞摄取 oxLDL 的量亦增加( P<0.05).而当 oxLDL 浓度继续增加时, 摄取
量并无明显增加( P>0.05),细胞损伤反而加重 ,活细胞率下降( P<0.05) 因此确立了
80ug/mloxLDL 下 U937 细胞摄取 oxLDL 的量作为下一步药效学研究的基础.
实验二 漏芦血清药及蜕皮甾酮对 U937 细胞摄取 oxLDL 的影响
本实验观察了不同浓度, 不同时间点漏芦血清药以及不同浓度的蜕皮甾酮对 U937 细胞
摄取 oxLDL 的影响. 取给药后 1.5h 的彼格犬血清, 以浓度为 5%, 10%, 15%, 20%来干预 U937
细胞对 oxLDL 的摄取 ,并分别与相同浓度空白血清组对照 ,结果显示 15%, 20%的漏芦血清
药可抑制 U937 细胞摄取 oxLDL (P<0.05),在此基础上 ,我们研究了 0.5h, 1.5h, 3h, 6h,
12h , 24h 的漏芦血清药对 U937 细胞摄取 oxLDL 的影响, 终浓度均为 15%, 与空白血清组对
照 ,结果显示 1.5h ,3h, 6h 的漏芦血清药可抑制 U937 细胞摄取 oxLDL (P<0.05);此外, 进
一步研究发现 ,终浓度分别为 25, 50, 100, 200mg/l 的蜕皮甾酮对 U937 细胞摄取 oxLDL 无
抑制作用 (P>0.05 ). 以上结果提示 ,漏芦可能通过抑制泡沫细胞形成过程中的单核细胞摄
取 oxLDL ,从而抑制 AS 形成 ;而蜕皮甾酮的原形成分可能对泡沫细胞的形成无抑制作用.
实验三 蜕皮甾酮对泡沫细胞形成过程中 CD36 表达的影响
本实验观察了不同浓度的蜕皮甾酮对泡沫细胞形成过程中 CD36 表达的影响, 通过
80ug/ml 的 oxLDL 作用于 U937 细胞建立泡沫细胞模型, 并以终浓度为 15%的 1.5h 漏芦血清
药为阳性对照组, 蜕皮甾酮组浓度分别为 25,50, 100, 200mg/l,结果显示, 蜕皮甾酮对
泡沫细胞形成过程中 CD36 的表达无抑制作用 (P>0.05).
研究结果表明:(1) 漏芦血清药具有抑制 AS 中泡沫细胞形成的作用.(2)不同浓度的
漏芦血清药对单核细胞摄取 oxLDL 的抑制作用不同,提示漏芦的抗 AS 作用可能与药物剂量
有关.(3) 不同时间点的漏芦血清药对单核细胞摄取 oxLDL 的抑制作用不同, 提示不同时间
点的漏芦血清药的药物有效成分群不同.(4) 蜕皮甾酮的原形成分可能对单核细胞源性泡沫
细胞的形成无抑制作用. 但并不能证明其在体内的代谢产物对泡沫细胞的形成无抑制作用.
Atherosclerosis is the major pathological progress in the cardio-cerebro vascular disease. It is
also well-known that atherosclerosis is closely related to lipoprotein metabolism. In particular,
oxidative modification of low density lipoprotein (LDL) cholesterol, is involved in early
development of atherosclerotic lesions through the formation of macrophage-derived foam cells.
These foam cells, which are a typical feature of atherosclerotic lesions, are characterized by
massive amounts of cholesterol esters. Cholesterol accumulation in these cells have been
demonstrated to be mediated primarily by uptake of oxidized low density lipoprotein (oxLDL)
via scavenger receptors, which unlike LDL receptors, are not downregulated by the celluar content
of cholesterol. CD36 , thought to be important receptors for oxLDL, belongs to the class B
scavenger receptor family. A critical regulator of CD36 expression is the nuclear hormone
receptor PPARγ can be upregulated during the formation of macrophage-derived foam cells . The
increased expression of CD36 on the cell surface leads to the recruitment of monocytes from the
circulation further the internalizationof oxLDL. Furthermore, the differentiating macrophages and
oxLDL may promote the development of atherosclerosis. Thus, macrophage, oxLDL and CD36
play important roles in the formation and development of atherosclerosis. They have been the
focus of research for many years.
We have found the contract of rhaponticum uniflorum can be inhibit the formation and
development of atherosclerosis in animal models, and we also found ecdysterone, the main
component in the root of rhaponticum uniflorum. In order to find the mechanism and the potential
components of the contract of rhaponticum uniflorum for the treatment of atherosclerosis, We
study the uptake of oxLDL and the expression of CD36 in foam cells in the following
experiments.
Our experiments included three parts.
First, we used fluorescein isocyanate (FITC) to label oxLDL . After incubation of U937
cells with different concentrations of labelled oxLDL, flow cytometry was applied to measure the
celluar uptake of oxLDL , and microscope to observe the configuration of the cells at the same
time. We found the increasing uptake of oxLDL was associated with the increasing concentrations
of oxLDL from 10ug/ml to 80ug/ml, and the cells incubated with 80ug/ml oxLDL uptook more
oxidized LDL than others P<0.05 . However, when we increased the concentrations of oxidized
LDL from 80ug/ml to 160ug/ml, we didn’t find the increasing uptake of oxLDL P>0.05 but
more injuried cells P<0.05 . Therefore, we choose 80ug/ml of oxLDL for the subsequent
pharmacodynamics study.
Second, We observed the uptake of oxLDL by U937 cells treated with drug dog serum of
different concentrations and different time after feeding it with rhaponticum uniflorum. We used
英文摘要 -5-
four concentrations of drug dog serum (5%,10%,15%,20%) to inhibit the celluar uptake of
oxLDL . In contrast with the same concentrations of dog serum control, 15% and 20% of drug dog
serum have the significant effects P<0.05 . Based on this result, We observed the different effects
of dog serum at 1.5h, 3h,6h,12h,24h after feeding it with rhaponticum uniflorum. The 1.5h, 3h,6h
drug dog serum showed significant effects P<0.05 . In the experiment, we also observed the
uptaken oxLDL by U937 cells treated with four concentrations of ecdysterone(25 50 100
200mg/l). However, we did not find that ecdysterone inhibited the uptaken oxLDL by U937 cells
P>0.05 . According to the experimental data , we deduce that rhaponticum uniflorum can
inhibit the macrophage uptake of oxLDL and reduce the formation of atherosclerosis, however,
ecdysterone had no significant effect on the formation of foam cells.
And in the third experiment, we replicated the monocyte-derived foam cell model by
incubating U937 cells with 80ug/ml oxL
AS 形成与脂质代谢异常有关 ,尤其与氧化型低密度脂蛋白( Oxidized Low Density
Lipoprotein, oxLDL)有关, oxLDL 被巨噬细胞清道夫受体(Scavenger, SR)所识别, 摄取,
且不受细胞内胆固醇的反馈抑制, 结果细胞内脂质大量积聚, 巨噬细胞转变成富含胆固醇酯
的泡沫细胞——AS 形成早期脂肪条纹的主要细胞类型 ;CD36 是 oxLDL 的主要受体,在泡沫
细胞形成过程中, oxLDL 首先作用于 CD36 受体, 然后通过激活核受体使 CD36 表达增加 ,促
进单核细胞分化成巨噬细胞并摄取 oxLDL 形成泡沫细胞; 而活化的巨噬细胞和 oxLDL 又能加
速 AS 的进展. 因此 ,巨噬细胞, oxLDL, CD36 在AS的发生发展中具有重要作用,也一直是
AS 研究的重点.
整体动脉粥样硬化动物模型研究表明,漏芦水提物可使 AS 病变减轻, 对祁州漏芦水煎
剂成分进行分析 ,漏芦含有多种化学成分, 研究者曾从漏芦根和叶中提取了蜕皮甾酮 ,产率
较高 .因此 ,为了深入研究漏芦的抗 AS 的作用机制及发现其可能的有效成分 ,我们在本课
题的前期研究基础上 ,进行了如下的实验研究, 旨在通过分析漏芦血清药及蜕皮甾酮对单核
细胞摄取 oxLDL 和 CD36 表达的影响 ,进一步证明漏芦抗 AS 的可能机制及对蜕皮甾酮做初步
的药效学筛选.
本研究分为三个部分:
实验一 荧光标记法检测 U937 细胞对 oxLDL 的摄取作用
本实验应用异硫氰酸荧光素( fluorescein isocyanate, FITC) 标记 oxLDL, 通过流式细胞
仪检测不同浓度 oxLDL 的作用下 U937 细胞摄取 oxLDL 的量 ,并在显微镜下观察 U937 细胞的
形态学改变和计算活细胞率. 结果发现: 在 10ug/ml 至 80ug/ml 浓度范围内, 随着 oxLDL 浓
度的增加 U937 细胞摄取 oxLDL 的量亦增加( P<0.05).而当 oxLDL 浓度继续增加时, 摄取
量并无明显增加( P>0.05),细胞损伤反而加重 ,活细胞率下降( P<0.05) 因此确立了
80ug/mloxLDL 下 U937 细胞摄取 oxLDL 的量作为下一步药效学研究的基础.
实验二 漏芦血清药及蜕皮甾酮对 U937 细胞摄取 oxLDL 的影响
本实验观察了不同浓度, 不同时间点漏芦血清药以及不同浓度的蜕皮甾酮对 U937 细胞
摄取 oxLDL 的影响. 取给药后 1.5h 的彼格犬血清, 以浓度为 5%, 10%, 15%, 20%来干预 U937
细胞对 oxLDL 的摄取 ,并分别与相同浓度空白血清组对照 ,结果显示 15%, 20%的漏芦血清
药可抑制 U937 细胞摄取 oxLDL (P<0.05),在此基础上 ,我们研究了 0.5h, 1.5h, 3h, 6h,
12h , 24h 的漏芦血清药对 U937 细胞摄取 oxLDL 的影响, 终浓度均为 15%, 与空白血清组对
照 ,结果显示 1.5h ,3h, 6h 的漏芦血清药可抑制 U937 细胞摄取 oxLDL (P<0.05);此外, 进
一步研究发现 ,终浓度分别为 25, 50, 100, 200mg/l 的蜕皮甾酮对 U937 细胞摄取 oxLDL 无
抑制作用 (P>0.05 ). 以上结果提示 ,漏芦可能通过抑制泡沫细胞形成过程中的单核细胞摄
取 oxLDL ,从而抑制 AS 形成 ;而蜕皮甾酮的原形成分可能对泡沫细胞的形成无抑制作用.
实验三 蜕皮甾酮对泡沫细胞形成过程中 CD36 表达的影响
本实验观察了不同浓度的蜕皮甾酮对泡沫细胞形成过程中 CD36 表达的影响, 通过
80ug/ml 的 oxLDL 作用于 U937 细胞建立泡沫细胞模型, 并以终浓度为 15%的 1.5h 漏芦血清
药为阳性对照组, 蜕皮甾酮组浓度分别为 25,50, 100, 200mg/l,结果显示, 蜕皮甾酮对
泡沫细胞形成过程中 CD36 的表达无抑制作用 (P>0.05).
研究结果表明:(1) 漏芦血清药具有抑制 AS 中泡沫细胞形成的作用.(2)不同浓度的
漏芦血清药对单核细胞摄取 oxLDL 的抑制作用不同,提示漏芦的抗 AS 作用可能与药物剂量
有关.(3) 不同时间点的漏芦血清药对单核细胞摄取 oxLDL 的抑制作用不同, 提示不同时间
点的漏芦血清药的药物有效成分群不同.(4) 蜕皮甾酮的原形成分可能对单核细胞源性泡沫
细胞的形成无抑制作用. 但并不能证明其在体内的代谢产物对泡沫细胞的形成无抑制作用.
Atherosclerosis is the major pathological progress in the cardio-cerebro vascular disease. It is
also well-known that atherosclerosis is closely related to lipoprotein metabolism. In particular,
oxidative modification of low density lipoprotein (LDL) cholesterol, is involved in early
development of atherosclerotic lesions through the formation of macrophage-derived foam cells.
These foam cells, which are a typical feature of atherosclerotic lesions, are characterized by
massive amounts of cholesterol esters. Cholesterol accumulation in these cells have been
demonstrated to be mediated primarily by uptake of oxidized low density lipoprotein (oxLDL)
via scavenger receptors, which unlike LDL receptors, are not downregulated by the celluar content
of cholesterol. CD36 , thought to be important receptors for oxLDL, belongs to the class B
scavenger receptor family. A critical regulator of CD36 expression is the nuclear hormone
receptor PPARγ can be upregulated during the formation of macrophage-derived foam cells . The
increased expression of CD36 on the cell surface leads to the recruitment of monocytes from the
circulation further the internalizationof oxLDL. Furthermore, the differentiating macrophages and
oxLDL may promote the development of atherosclerosis. Thus, macrophage, oxLDL and CD36
play important roles in the formation and development of atherosclerosis. They have been the
focus of research for many years.
We have found the contract of rhaponticum uniflorum can be inhibit the formation and
development of atherosclerosis in animal models, and we also found ecdysterone, the main
component in the root of rhaponticum uniflorum. In order to find the mechanism and the potential
components of the contract of rhaponticum uniflorum for the treatment of atherosclerosis, We
study the uptake of oxLDL and the expression of CD36 in foam cells in the following
experiments.
Our experiments included three parts.
First, we used fluorescein isocyanate (FITC) to label oxLDL . After incubation of U937
cells with different concentrations of labelled oxLDL, flow cytometry was applied to measure the
celluar uptake of oxLDL , and microscope to observe the configuration of the cells at the same
time. We found the increasing uptake of oxLDL was associated with the increasing concentrations
of oxLDL from 10ug/ml to 80ug/ml, and the cells incubated with 80ug/ml oxLDL uptook more
oxidized LDL than others P<0.05 . However, when we increased the concentrations of oxidized
LDL from 80ug/ml to 160ug/ml, we didn’t find the increasing uptake of oxLDL P>0.05 but
more injuried cells P<0.05 . Therefore, we choose 80ug/ml of oxLDL for the subsequent
pharmacodynamics study.
Second, We observed the uptake of oxLDL by U937 cells treated with drug dog serum of
different concentrations and different time after feeding it with rhaponticum uniflorum. We used
英文摘要 -5-
four concentrations of drug dog serum (5%,10%,15%,20%) to inhibit the celluar uptake of
oxLDL . In contrast with the same concentrations of dog serum control, 15% and 20% of drug dog
serum have the significant effects P<0.05 . Based on this result, We observed the different effects
of dog serum at 1.5h, 3h,6h,12h,24h after feeding it with rhaponticum uniflorum. The 1.5h, 3h,6h
drug dog serum showed significant effects P<0.05 . In the experiment, we also observed the
uptaken oxLDL by U937 cells treated with four concentrations of ecdysterone(25 50 100
200mg/l). However, we did not find that ecdysterone inhibited the uptaken oxLDL by U937 cells
P>0.05 . According to the experimental data , we deduce that rhaponticum uniflorum can
inhibit the macrophage uptake of oxLDL and reduce the formation of atherosclerosis, however,
ecdysterone had no significant effect on the formation of foam cells.
And in the third experiment, we replicated the monocyte-derived foam cell model by
incubating U937 cells with 80ug/ml oxL
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[36] Shi W. Paradoxial reduction of fatty streak formation in mice lacking endothelial nitric oxide
synthase. Circulation, 2002,105:2078-2082
[37] Daugherty A, Dun JL, Rateri DL, et al. Myeloperoxidase, a catalyst for lipoprotein
oxidation ,is expressed in human atherosclerotic lesion. J Clin Invest, 1994,94:437-444
[38] Brennan ML. Increased atherosclerosis in myeloperoxidase-deficient mice. J Clin Invest,
2001,107:419-430
[39] Steinberg D, Witztum JL. Is the oxidative modification hypothesis relevant to human
atherosclerosis? Do the antioxidant trials conducted to the date refute the hypothesis?
Circulation,2002,105:2107-2111
[40] Scheidegger KJ, Butler S, Witztum JL. Angiotensin ?? increases macrophage-mediated
modification of low density lipoprotein via a lipoxygenase-dependent pathway. J Biol
Chem,1997,272:21609-21615
[41] Hayek T. The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin ??
receptor antagonist, losartan, inhibit LDLoxidation and attenuate atherosclerosis independent of
lowering blood pressure in apolipoprotein E deficient mice. Cardiovasc Res,1999,44:579-587
[42] Boullier A. Scavenger receptors, oxidized LDL, and the atherosclerosis. Ann NY Acad Sci,
2001,947:214-222
-16- 漏芦抑制单核细胞源性泡沫细胞形成的机理研究
[43] Febbraio M, Hajjar DP, Silverstein RL. CD36: a class B scavebger receptor involved in
angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest,
2001,108:785-791
[44] Shaw P. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic
clearance, and protective immunity. J Clin Invest, 2000,105:1731-1740
[45] Krieger M. Scavenger receptor class B type ? is a multiligand HDL receptoe thet influences
diverse physiologic system. J Clin Invest, 2001,108:793-797
[46] Febbraio M, Podrez EA, Smith JD, et al. Targeted disruption of the class B scavenger receptor
CD36 protects against atherosclerotic lesion development in mice . J Clin Invest,
2000,105:1049-1056
[47] Tontonoz P, Nagy L, Alvarez JG. et al. PPARγ promotes monocyte-macrophage
differentiation and uptake of oxidized LDL. Cell, 1998,93:241-252
[48] Nagy L, Tontonoz P, Alvarez JG. et al. LDL regulates macrophage gene expression through
ligand activation of PPARγ. Cell, 1998,93:229-240
[49] 田林郁,周东. 动脉粥样硬化与清道夫受体.国外医学脑血管疾病分册,2001,9(4) 202-206
[50] 杨向东,李红霞,王抒,等.CD36 介导氧化型低密度脂蛋白诱导 U937 细胞泡沫化和凋亡.中
国动脉硬化杂志,2000,8(4):315-318
[51] Chen W, Sliver DJ, Smith JD. et al. Scavenger receptor-B? inhibits ATP-binding cassette
transporter 1-mediated cholesterol efflux in macrophages. J Biol Chem, 2000,275:30794-30800
[52] Braun A. Loss of SR-B? expression leads to the early onset of occlusive atherosclerotic
coronay artery disease, spontaneous myocardial infarction, severe cardiac dysfunction, and
premature death in apoplipoprotein E-deficient mice. Circ Res, 2002,90:270-276
[53] Andrew CL, Christopher KG. The macrophage foam cell as a target for therapeutic
intervention. Nature Med, 2002,8:1235-1242
[54] Brewer HB. The lipid-laden foam cell: An enclusive target for the therapeutic intervention. J
Clin Invest, 2000,105:703-705
[55] Accad M. Massive zanthomatosis and altered composition of atherosclerotic lesions in
hyperlipidemic mice lacking acyl CoA: cholesterol acytransferase 1. J Clin Invest,
2000,105;711-719
[56] Fazio S. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages.
J Clin Invest, 2001,107:163-171
[57] Escary JL. Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression
in macrophages. J Lipid Res, 1999,40:397-404
[58] Kusunoki J. Acyl-CoA: cholesterol acyltransferase inhibition reduces atherosclerosis in
apoplipoprotein E-deficient mice. Circulation, 2001,103:2604-2609
[59] Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content
membranes, cells,and blood. Proc Natl Acad Sci USA,1999,96:11041-11048
[60] Chawla A, Repa J, Evans R, et al. Nuclear receptors and lipid physiology: Opening the
综述一 巨噬细胞源性泡沫细胞的形成及其治疗的研究进展 -17-
X-Files. Science, 2001,294:1866-1870
[61] Laffitte BA. LXRs control lipid-inducible expression of the apolipoprotein Egene in
mysrophsges and adipocytes. Proc Natl Acad Sci USA, 2001,98:507-512
[62] Repa JJ. Regulation of mouse sterol regulatory element-binding protein-1c (SREBP-1c) by
oxysterol receptors LXR-α and LXR-β. Gene Dev, 2000,14:2819-2830
[63] Chawla A. A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux
and atherogenesis. Mol Cell,2001,7:161-171
[64] Tall AR, Wang N. Tangier disease as a test of the reverse cholesterol transport hypothesis. J
Clin Invest, 2000,106:1205-1207
[65] Aiello RJ. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in
macrophages. Arterioscler Thromb, 2002,22:630-637
[66] Vaneck M. leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage
recruitment into tissues. Proc Natl Acad Sci USA, 2002,99:6298-6903
[67] Singaraja RR. Increased ABCA1 activity protects against atherosclerosis. J Clin Invest,
2002,110:35-42
[68] Clee SM. Common genetic variation in ABCA1 is associated with altered lipoprotein levels
and a modified risk for coronary artery disease. Circulation,2001,103:1198-1205
[69] Claudel T. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of
the retinoid X receptor. Proc Natl Acad Sci USA, 2001,98:2610-2615
[70] Joseph SB. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc
Natl Acad Sci USA, 2002,99:7604-7609
[71] Goldberg IJ, Merkel M. Lipoprotein lipase: physiology, biochemistry, and molechle biology.
Front Biosci, 2001,6:388-405
[72] Mead JR, Ramji DP. The pivotal role of lipoprotein lipase in atherosclerosis. Carsiovasc
Res,2002,55:261-269
[73] Yagyu H. Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein
E knockout mice. J Lipid Res, 1999,40:1677-1685
[74] Wilscon K, Fry GL, Chappell DA, et al. Macrophage-specific expression of human
lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein E knockout mice but not
in C57BL/6 mice. Arterioscler Thromb Vasc Biol, 2001,21:1809-1815
[75] Babaev VR. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis
in vivo. J Clin Invest, 1999,103:1697-1705
[76] Wang Y, Oram JF.Unsatruated fatty acids inhibit cholesterol efflux from macrophages by
increasing degradation of ATP-binding cassette transporter A1. J Biol Chem, 2002,277: 5692-5697
[77] Barbier O. Pleiotropic actions of peroxisome proliferators-activated receptors in lipid
metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol,2002,22:717-726
[78] Oliver WR. A selective peroxisome proliferators-activated receptors delta agonist promotes
reverse aholesterol transport. Proc Natl Acad Sci USA. 2001,98:5306-5311
-18- 漏芦抑制单核细胞源性泡沫细胞形成的机理研究
[79] Daugherty A. The effects of total lymphocyte deficiency on the extent of iatherosclerosis in
apolipoprotein E-/- mice. J Clin Invest,1997,100:1575-1580
[80] Song L, Leung C, Schindler C. Lymphocytes are impotant inearly atherosclerosis. J Clin
Invest,2001,108:251-259
[81] Reardon CA. Effect of immune deficiency on lipoproteins and atherosclerosis in male
apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol, 2001,21:1011-1016
[82] Dansky HM, Charlton SA, Harper MM, et al. T and B lymphocytes play a minor role in
atherosclerosis plaque formation in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci ,
1997,94:4646-4662
[83] Horkko S. Immunological responses to oxidized LDL. Free Radic Biol Med,
2000,28:1771-1779
[84] Panousis CG, Zuckerman SH. Interferon-γ induces downregulation of Tangier disease gene
(ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc
Biol, 2000,20:1565-1571
[85] Gupta S. IFN-γ potentiates atherosclerosis in ApoE knockout mice. J Clin Invest,
1997,99:2752-2761
[86] Pinderski LJ. Overexpression of interleukin-10 by activated T lymphocytes inhibits
atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and the macrophage
phenotypes. Circ Res,2002,90:1064-1071
[87] Mallat Z. Protective role of interleukin-10 in atherosclerosis. Circ Res, 1999,85:17-24
[88] Palinski W, Tsimikas S. Immunomodulatory effects of ststins: mechanisms and potential
impact on arteriosclerosis. J Am Soc Nephrol, 2002,13:1673-1681
[89] Yasojima K, Schwab C, Mcgeer EG, et al. Generation of C-reactive protein and complement
components in atherosclerotic plaque. Am J Pathol, 2001,158:1039-1051
[90] Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferators-activated receptor gamma
and metabolic disease. Annu Rev Biochem, 2001,70:341-367
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homeostasis and inflammatory responses of macrophages. Curr Opin Lipidol, 2002,13:305-312
[92] Haffner SM. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular
disease in patients with type 2 diabets mellitus. Circulation, 2002,106:679-684
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synthase. Circulation, 2002,105:2078-2082
[37] Daugherty A, Dun JL, Rateri DL, et al. Myeloperoxidase, a catalyst for lipoprotein
oxidation ,is expressed in human atherosclerotic lesion. J Clin Invest, 1994,94:437-444
[38] Brennan ML. Increased atherosclerosis in myeloperoxidase-deficient mice. J Clin Invest,
2001,107:419-430
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atherosclerosis? Do the antioxidant trials conducted to the date refute the hypothesis?
Circulation,2002,105:2107-2111
[40] Scheidegger KJ, Butler S, Witztum JL. Angiotensin ?? increases macrophage-mediated
modification of low density lipoprotein via a lipoxygenase-dependent pathway. J Biol
Chem,1997,272:21609-21615
[41] Hayek T. The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin ??
receptor antagonist, losartan, inhibit LDLoxidation and attenuate atherosclerosis independent of
lowering blood pressure in apolipoprotein E deficient mice. Cardiovasc Res,1999,44:579-587
[42] Boullier A. Scavenger receptors, oxidized LDL, and the atherosclerosis. Ann NY Acad Sci,
2001,947:214-222
-16- 漏芦抑制单核细胞源性泡沫细胞形成的机理研究
[43] Febbraio M, Hajjar DP, Silverstein RL. CD36: a class B scavebger receptor involved in
angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest,
2001,108:785-791
[44] Shaw P. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic
clearance, and protective immunity. J Clin Invest, 2000,105:1731-1740
[45] Krieger M. Scavenger receptor class B type ? is a multiligand HDL receptoe thet influences
diverse physiologic system. J Clin Invest, 2001,108:793-797
[46] Febbraio M, Podrez EA, Smith JD, et al. Targeted disruption of the class B scavenger receptor
CD36 protects against atherosclerotic lesion development in mice . J Clin Invest,
2000,105:1049-1056
[47] Tontonoz P, Nagy L, Alvarez JG. et al. PPARγ promotes monocyte-macrophage
differentiation and uptake of oxidized LDL. Cell, 1998,93:241-252
[48] Nagy L, Tontonoz P, Alvarez JG. et al. LDL regulates macrophage gene expression through
ligand activation of PPARγ. Cell, 1998,93:229-240
[49] 田林郁,周东. 动脉粥样硬化与清道夫受体.国外医学脑血管疾病分册,2001,9(4) 202-206
[50] 杨向东,李红霞,王抒,等.CD36 介导氧化型低密度脂蛋白诱导 U937 细胞泡沫化和凋亡.中
国动脉硬化杂志,2000,8(4):315-318
[51] Chen W, Sliver DJ, Smith JD. et al. Scavenger receptor-B? inhibits ATP-binding cassette
transporter 1-mediated cholesterol efflux in macrophages. J Biol Chem, 2000,275:30794-30800
[52] Braun A. Loss of SR-B? expression leads to the early onset of occlusive atherosclerotic
coronay artery disease, spontaneous myocardial infarction, severe cardiac dysfunction, and
premature death in apoplipoprotein E-deficient mice. Circ Res, 2002,90:270-276
[53] Andrew CL, Christopher KG. The macrophage foam cell as a target for therapeutic
intervention. Nature Med, 2002,8:1235-1242
[54] Brewer HB. The lipid-laden foam cell: An enclusive target for the therapeutic intervention. J
Clin Invest, 2000,105:703-705
[55] Accad M. Massive zanthomatosis and altered composition of atherosclerotic lesions in
hyperlipidemic mice lacking acyl CoA: cholesterol acytransferase 1. J Clin Invest,
2000,105;711-719
[56] Fazio S. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages.
J Clin Invest, 2001,107:163-171
[57] Escary JL. Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression
in macrophages. J Lipid Res, 1999,40:397-404
[58] Kusunoki J. Acyl-CoA: cholesterol acyltransferase inhibition reduces atherosclerosis in
apoplipoprotein E-deficient mice. Circulation, 2001,103:2604-2609
[59] Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content
membranes, cells,and blood. Proc Natl Acad Sci USA,1999,96:11041-11048
[60] Chawla A, Repa J, Evans R, et al. Nuclear receptors and lipid physiology: Opening the
综述一 巨噬细胞源性泡沫细胞的形成及其治疗的研究进展 -17-
X-Files. Science, 2001,294:1866-1870
[61] Laffitte BA. LXRs control lipid-inducible expression of the apolipoprotein Egene in
mysrophsges and adipocytes. Proc Natl Acad Sci USA, 2001,98:507-512
[62] Repa JJ. Regulation of mouse sterol regulatory element-binding protein-1c (SREBP-1c) by
oxysterol receptors LXR-α and LXR-β. Gene Dev, 2000,14:2819-2830
[63] Chawla A. A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux
and atherogenesis. Mol Cell,2001,7:161-171
[64] Tall AR, Wang N. Tangier disease as a test of the reverse cholesterol transport hypothesis. J
Clin Invest, 2000,106:1205-1207
[65] Aiello RJ. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in
macrophages. Arterioscler Thromb, 2002,22:630-637
[66] Vaneck M. leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage
recruitment into tissues. Proc Natl Acad Sci USA, 2002,99:6298-6903
[67] Singaraja RR. Increased ABCA1 activity protects against atherosclerosis. J Clin Invest,
2002,110:35-42
[68] Clee SM. Common genetic variation in ABCA1 is associated with altered lipoprotein levels
and a modified risk for coronary artery disease. Circulation,2001,103:1198-1205
[69] Claudel T. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of
the retinoid X receptor. Proc Natl Acad Sci USA, 2001,98:2610-2615
[70] Joseph SB. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc
Natl Acad Sci USA, 2002,99:7604-7609
[71] Goldberg IJ, Merkel M. Lipoprotein lipase: physiology, biochemistry, and molechle biology.
Front Biosci, 2001,6:388-405
[72] Mead JR, Ramji DP. The pivotal role of lipoprotein lipase in atherosclerosis. Carsiovasc
Res,2002,55:261-269
[73] Yagyu H. Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein
E knockout mice. J Lipid Res, 1999,40:1677-1685
[74] Wilscon K, Fry GL, Chappell DA, et al. Macrophage-specific expression of human
lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein E knockout mice but not
in C57BL/6 mice. Arterioscler Thromb Vasc Biol, 2001,21:1809-1815
[75] Babaev VR. Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis
in vivo. J Clin Invest, 1999,103:1697-1705
[76] Wang Y, Oram JF.Unsatruated fatty acids inhibit cholesterol efflux from macrophages by
increasing degradation of ATP-binding cassette transporter A1. J Biol Chem, 2002,277: 5692-5697
[77] Barbier O. Pleiotropic actions of peroxisome proliferators-activated receptors in lipid
metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol,2002,22:717-726
[78] Oliver WR. A selective peroxisome proliferators-activated receptors delta agonist promotes
reverse aholesterol transport. Proc Natl Acad Sci USA. 2001,98:5306-5311
-18- 漏芦抑制单核细胞源性泡沫细胞形成的机理研究
[79] Daugherty A. The effects of total lymphocyte deficiency on the extent of iatherosclerosis in
apolipoprotein E-/- mice. J Clin Invest,1997,100:1575-1580
[80] Song L, Leung C, Schindler C. Lymphocytes are impotant inearly atherosclerosis. J Clin
Invest,2001,108:251-259
[81] Reardon CA. Effect of immune deficiency on lipoproteins and atherosclerosis in male
apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol, 2001,21:1011-1016
[82] Dansky HM, Charlton SA, Harper MM, et al. T and B lymphocytes play a minor role in
atherosclerosis plaque formation in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci ,
1997,94:4646-4662
[83] Horkko S. Immunological responses to oxidized LDL. Free Radic Biol Med,
2000,28:1771-1779
[84] Panousis CG, Zuckerman SH. Interferon-γ induces downregulation of Tangier disease gene
(ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc
Biol, 2000,20:1565-1571
[85] Gupta S. IFN-γ potentiates atherosclerosis in ApoE knockout mice. J Clin Invest,
1997,99:2752-2761
[86] Pinderski LJ. Overexpression of interleukin-10 by activated T lymphocytes inhibits
atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and the macrophage
phenotypes. Circ Res,2002,90:1064-1071
[87] Mallat Z. Protective role of interleukin-10 in atherosclerosis. Circ Res, 1999,85:17-24
[88] Palinski W, Tsimikas S. Immunomodulatory effects of ststins: mechanisms and potential
impact on arteriosclerosis. J Am Soc Nephrol, 2002,13:1673-1681
[89] Yasojima K, Schwab C, Mcgeer EG, et al. Generation of C-reactive protein and complement
components in atherosclerotic plaque. Am J Pathol, 2001,158:1039-1051
[90] Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferators-activated receptor gamma
and metabolic disease. Annu Rev Biochem, 2001,70:341-367
[91] Klappacher GW, Glass CK. Roles of proliferators-activated receptor gamma in lipid
homeostasis and inflammatory responses of macrophages. Curr Opin Lipidol, 2002,13:305-312
[92] Haffner SM. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular
disease in patients with type 2 diabets mellitus. Circulation, 2002,106:679-684