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LXR激动剂对ApoE基因敲除小鼠动脉粥样硬化的作用

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2011年第2期
页码:
156-160
栏目:
基础研究
出版日期:
2010-12-10

文章信息/Info

Title:
Effect of liver X-receptor agonist on atherosclerosis of apolipoprotein E-deficient mice
作者:
陈江红; 张铮; 张申伟; 潘云虎; 曹丰; 郭文怡
第四军医大学西京医院心血管内科，陕西 西安 710032
Author(s):
CHEN Jiang-hong;  ZHANG Zheng;  ZHANG Shen-wei;  PAN Yun-hu;  CAO Feng;  GUO Wen-yi
Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China
关键词:
肝孤核受体; 三磷酸腺苷结合盒转运体A1; 载脂蛋白E 基因敲除小鼠; 动脉粥样硬化
Keywords:
liver X-receptor agonist;  ATP-binding cassette transporter A1;  apolipoprotein E gene knockout mice;  atherosclerosis
分类号:
R972
DOI:
-
文献标识码:
A
摘要:
目的: 观察肝孤核受体(LXR)激动剂（T-0901317）对ApoE基因敲除小鼠［ApoE(-/-)］主动脉结构和血管活性的影响，探讨LXR激动剂对抑制动脉粥样硬化(AS)病变形成的作用及潜在机制。方法： 12周龄ApoE基因敲除小鼠随机分为AS模型对照组（AS组）与LXR激动剂干预组(AS+LXR组)，将有相同遗传背景的同龄正常C57BL/6J小鼠分为正常对照组（CON组）与单纯药物干预组（CON+LXR组）。CON+LXR组、AS+LXR组LXR激动剂连续灌胃6周，剂量为10 mg/（kg·d）。AS组、CON组灌服等量生理盐水。各组小鼠在处理6周后进行外周血采集检测血脂，并分离主动脉, 透射电镜观察血管超微结构，Western blot测定主动脉壁中三磷酸腺苷结合盒转运体A1（ABCA1）蛋白的表达水平。结果： AS+LXR组血浆总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)均显著低于AS组（P<0.01）,高密度脂蛋白胆固醇（HDL-C）高于AS组（P<0.05）。AS组主动脉内膜呈明显粥样硬化斑块形成特点，AS+LXR组内皮变性坏死比AS组明显减低。与AS组比较，AS+LXR组的AS病变面积显著降低,同时动脉壁中ABCA1的表达显著增强。结论： LXR激动剂T-0901317能够显著改善血脂，对主动脉内膜超微结构有良好的修复和保护作用，对高脂饲养的ApoE基因敲除小鼠的AS形成具有抑制作用，其作用机制可能与LXR激动剂上调动脉壁巨噬细胞中ABCA1蛋白的表达、增强胆固醇逆转运有关。
Abstract:
AIM: To observe the effects and mechanisms of liver X-receptor (LXR) agonist (T-0901317) on aorta structure, blood vessel activity and atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. METHODS: Twelve-week-old ApoE-/- mice were divided randomly into model group (fed with saline, AS) and LXR agonist group (fed with LXR agonist, AS+L), and normal C57BL/6J mice were randomized into control group (fed with saline, C) and singlet intervention group (fed with LXR agonist, L). LXR agonist (T-0901317) was orally administered daily at a dose of 10 mg/kg for 6 weeks. Plasma lipids were determined after 6 weeks treatment. Aortas were isolated and observed by transmission electron microscopy and expressions of ATP-binding cassette transporter A1 (ABCA1) in the aortic atherosclerotic lesions were detected by Western blot method. RESULTS: Levels of total cholesterol, triglyceride and high-density lipoprotein cholesterol in AS+L group were significantly lower than those in AS group (P<0.05). LXR agonist inhibited degeneration and necrosis of endothelium and significantly reversed the development of atherosclerotic lesions compared with that in AS group. Expressions of ABCA1 in the artery wall were elevated in AS+L group compared with those in AS control. CONCLUSION: LXR agonist significantly decreases the level of serum lipids and reverses the development of atherosclerotic lesions in ApoE-/- mice. It is suggested that LXR agonist has favorable effects on artery endothelium repair, possibly by enhancing the reverse cholesterol transport in vivo via upregulating ABCA1 expression within the aorta wall.

参考文献/References

[1]Brooks WA, Marcil M, Clee S M, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency［J］. Nat Genet, 1999, 22(4):336-345.

[2]Plump AS, Smith JD, Hayek T, et al. Severe hypercholes-terolemia and atheroslerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells［J］. Cell, 1992, 71(10):343-353.

[3]Zhang SH, Reddick RL, Piedrahita JA, et al. Sponta-neous hypercholesterolemia and arterial lesions in mice lacking aopolipoprotein E［J］. Science, 1992, 258(5081):468-471.

[4]刘龙涛,张文高,郑广娟. 载脂蛋白E 基因敲除小鼠在动脉粥样硬化研究中的应用［J］ . 山东生物医学工程, 2002, 21(4):39-42,31.

[5]Cha JY, Repa JJ. The liver X receptor (LXR) and hepatic lipogenesis.The carbohydrate-response element -binding protein is a target gene of LXR［J］. J Biol Chem, 2007, 282(1):743-751.

[6]Zhou J, Febbraio M, Wada T, et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis［J］. Gastroenterology, 2008, 134(2):556-567.

[7]Jaber J, Murin J, Kinova S, et al. The role of infection and inflammation in the pathogenisis of atherosclerosis［J］. Vinitr Lek, 2002, 48(7):657-666.

[8]Haghpassand M, Bourassa PA, Francone OL, et al. Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels［J］. Clin Invest, 2001, 108(6):1315-1320.

[9]van Eck M, Bos IS, Kaminski WE, et al. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues［J］. Proc Natl Acad Sci U S A, 2002, 99(19):6298-6303.

[10]Joyce CW, AmarMJ, Lambert G, et al. The ATP binding cassette trans-porter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice［J］. Proc Natl Acad Sci U S A, 2002, 99(1):407-412.

[11]Singaraja RR, Fievet C, Castro G, et al. Increased ABCA1 activity protects against atherosclerosis［J］. Clin Invest, 2002, 110(1): 35-42.

[12]Terasaka N, Hiroshima A, Koieyama T, et al. T-0901317, a synthetic liver X receptor ligand, inhibits development of athero-sclerosis in LDL receptor-deficient mice［J］. FEBS Lett, 2003, 11(1-3):536.

[13]Swahn BM, Macsari I, Viklund J, et al. Liver X receptor agonists with selectivity for LXRbeta; N-aryl-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides［J］. Bioorg Med Chem Lett, 2009, 19(7):2009-2012.

[14]Schwart K, Lawn RM, Wade DP. ABC1 gene expression and ApoA1 mediated cholesterol sterol efflux are regulated by LXR［J］. Biochem Biophys Res Commun, 2000, 274(3):794-802.

[15]Wade DP, Owen JS. Regulation of the cholesterol efflux gene ABCA1［J］. Lancet, 2001, 357(9251):161-163.

[16]Huuskonen J, Vishnu M, Pullinger CR, et al. Regulation of ATP-binding cassette transporter A1 transcription by thyroid hormone receptor［J］. Biochemistry, 2004, 43(6):1626-1632.

[17]Luo Y, Tall AR.Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element［J］. J Clin Invest, 2000, 105(4):513-520.

[18]Lawn RM, Wade DP, Couse TL, et al. Localization of human ATP binding cassette transporter1(ABCA1) in normal and atherosclerotic tissue［J］. Ateroscler Thromb Vasc Biol, 2001, 21(3):378-385.

[19]Langmann T, Klucken J, Reil M, et al. Molecular cloning of the human ATP binding cassette transporter1(h ABCA1): evidence for sterol dependent regulation in macrophages［J］. Biochem Biophys Res Commun, 1999, 257(1):29-33.

备注/Memo

备注/Memo:
收稿日期：2010-03-30.通讯作者：郭文怡，主任医师， 主要从事冠心病介入治疗的研究Email:guowenyi@tom.com 共同通讯作者：曹丰，教授，主要从事分子影像及干细胞治疗的研究Email:wind8828@gmail.com 作者简介：陈江红，硕士生Email：yo-yo.chenjh@sohu.com
更新日期/Last Update: 2010-12-10