以膜转运蛋白为靶点的药物筛选模型的构建与应用研究
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摘要
动脉粥样硬化(atherosclerosis, AS)是缺血性心脑血管疾病(如冠心病、心绞痛、心肌梗塞、脑卒中等)共同的病理生理基础,而外周细胞内胆固醇代谢障碍是动脉粥样硬化的重要发病机制。过量胆固醇从肝外组织中的清除是预防和治疗AS的关键步骤。ATP结合盒转运体Al (ATP-binding cassette transporter Al, ABCA1)是ATP结合盒转运体超家族成员之一,是一种重要的以ATP为能源转运各种离子、脂类等细胞代谢物的膜转运蛋白。ABCA1可介导细胞内磷脂和游离胆固醇转运至贫脂或无脂的载脂蛋白A-Ⅰ(apolipoprotein A-Ⅰ, apoA-I),从而促进高密度脂蛋白(high density lipoprotein, HDL)生成。此过程被誉为脂质外流的限速步骤,在胆固醇逆转运过程中发挥重要作用。
研究发现,ApoA-I与ABCA1是类似于一种受体-配体的相互作用来发挥其功能的。据此原理,我们建立了基于与ABCA1结合的ApoA-I的cell-ELISA-like的高通量筛选模型,对本实验室的合成和天然产物化合物库进行大规模筛选,以其发现调节ABCA1活性的化合物,为治疗抗动脉粥样硬化的新型先导化合物的出现奠定基础。
本研究采用trizol法提取MRC-5细胞总RNA,经逆转录合成cDNA。以此cDNA为模板,采用高保真的Prime Star DNA聚合酶和分段PCR的策略,进行限制性内切酶分析后,我们从其内部选择了xho I、EcoR I、Nhe I三个酶切位点,ABCA1 cDNA两端分别添加了sac I和salⅠ酶切位点,分段克隆了1823bp,1061 bp,2750 bp和1664bp的片段,与pMD-19T simple载体连接并测序正确后,酶切后与真核表达载体pIRES2-EGFP载体连接构建成功ABCA1 (cDNA全长6789bp)的真核表达载体。将构建成功的载体转入CHO细胞,以G418 500μg/ml的浓度筛选出稳定表达ABCA1的单克隆细胞,以此单克隆细胞包被96孔板,加入8μg/ml ApoA-Ⅰ为配基,孵育2小时后,依次加入anti-ApoA-I一抗和相应二抗,TMB显色,450nm测定OD值。
经各项条件优化后,建立起以ABCA1为靶标的cell-ELISA-like高通量筛选模型,以ABC家族抑制剂格列本脲为阳性药对模型进行评价,接着对本室2600个天然和合成化合物库进行了筛选,从中发现了一种氧杂葸酮(口山酮)类化合物№2026791具有明显的上调ABCA1活性的作用,其在50μM时上调活性达30%。流式细胞术和western-blot分析均证实了№2026791增加了细胞表面ApoA-I的结合,证实№2026791可能为上调ABCA1介导的脂质外流活性的激动剂。
本研究建立的ABCA1为靶标的cell-ELISA-like高通量新药筛选模型,可用来筛选对ABCA1脂质外流活性起调节作用的合成化合物及天然产物提取物,具有一定的创新性和广泛的实用性。筛选得到的阳性化合物№2026791经多种方法证实,具有潜在提高ABCA1脂质外流活性的能力,可为新型抗AS的先导化合物的发现创造了条件。
钠钾ATP酶(Na/K-ATPase),又称钠泵,是P型ATP酶的一员,存在于大多数动物细胞的细胞质膜中。早在1957年Skou等人发现其可作为ATP能量驱动的离子泵之后,它的离子转运功能及其相关的调节已得到深入的研究。虽然早期的研究表明此酶同样也在基因的表达和细胞的生长方面扮演重要角色,但直到近几年才发现其可以组装多种信号分子形成信号转导复合物,引发信号转导的级联反应,并借以对不同蛋白的功能进行调节。在质膜上它能够与Src结合形成二元受体并与小窝蛋白一起组装成信号转导复合物,借助Src激酶反式激活内皮生长因子受体EGFR,激活胞内信号转导的级联反应,参与细胞的生长和调控。研究钠钾ATP酶及其信号转导机制将有助于发现在肿瘤和心血管治疗方面找到新的药物靶点。
本研究采用密度梯度离心的方法,从猪肾中分离出了高纯度高活性的Na/K-ATPase蛋白。采用酶学的方法建立以Na/K-ATPase为靶点的高通量筛选模型,以测定其水解产生的Pi的量反映其活性的大小。以此模型对本室化合物库中2600个化合物进行了高通量筛选,共得到18个阳性化合物,均显示出对Na/K-ATPase有一定的抑制作用。其中6个具有相似结构,同属羟基口山酮类化合物。构效关系研究表明羟基的数目和位置对其活性至关重要。量效关系曲线表明,此类化合物不同于强心苷类代表药物乌本苷(ouabain),其对Na/K-ATPase呈现双相抑制作用,说明可能作用于Na/K-ATPase的两个不同构象。已经进行的实验研究发现,这一类化合物更易结合Na/K-ATPase的E1样构象,不同于ouabain的E2构象。并且这类化合物可以在一定程度拮抗ouabain与Na/K-ATPase的结合。显示了其作为强心苷类物质的潜在拮抗作用。
新发现的这类羟基口山酮类化合物作为Na/K-ATPase的新配体,将有助于研究Na/K-ATPase构象的变化和离子转运、信号转导等生理功能,有助于更好的理解Na/K-ATPase在机体中或细胞的正常生理活动中扮演的角色和重要作用。
Atherosclerosis is the principal pathogenesis for many critical cardiovascular diseases (e.g., coronary heart disease, angina pectoris, myocardial infarction and stroke).The characteristic component of the atherosclerotic plaque is the macrophage derived foam cell. Intracellular free cholesterol can be toxic to the cell and therefore an efficient cholesterol efflux mechanism in macrophage is mandatory to prevent cholesterol accumulation. The ATP-binding cassette transporter A1 (ABCA1), which belongs to a superfamily of ATP-binding cassette transporters (ABCs), mediates the rate-controlling step in the HDL particle formation and in the assembly of free cholesterol and phospholipids with lipid-poor apolipoprotein A-I (apoA-I). Several laboratories have demonstrated that lipid-poor apolipoprotein A-I (apoA-I) can interacts with ABCA1 to mediate cellular cholesterol and nascent HDL assembly, which suggests a possible receptor-ligand type interaction between ABCA1 and apoA-I. In the current study, a high-throughput assay cell-ELISA-like method for ABCA1 regulators targeted at the binding apoA-I was developed and used for screening a synthetic and natural compound library. The cell-ELISA based high throughput screen is conducted in a 96-well format using CHO cells stably transfected with ABCA1 pIRE2-EGFP expression vector and calibrated with reference ABCA1 inhibitor Glibenclamide. Among 2600 compounds,1 xanthone compound 2026791 was picked up as hits by the highthroughput screening assay, and the compound was further identified as potential accelerator of cholesterol efflux via ABCA1 by flow cytometry assay and western blot analysis.
Na,K-ATPase is an integral membrane protein found in most mammalian cells. It was initially discovered as an energy transducing ion pump that transports 3 Na+out and 2 K+ into the cell by hydrolysis of one molecule of ATP. The ligands of Digitalis-like glycosides have been reported to be the specific inhibitors of Na,K-ATPase which are most accessible to the E2-P form on the extracellular side, resulting in the specific inhibition of ATP hydrolysis and cation transport. Recently we and others have found that Na,K-ATPase can interact with Src to form a functional signaling compex which can be as the receptor of endogenous cardiotonic glycosides and mediate extracellular signal transduction into the cell so as to regulate cell growth and expression of various genes. In order to develop new promising chemicals targeted at Na,K-ATPase which benefit the cardiovascular diseases and cancer, A high throughput screen assay in a multiwell format was established. A library of 2600 compounds was screened using the developed assay, and a class of hydroxyxanthones with different inhibition of the Na,K-ATPase was identified. Further study of one compound MB5 indicate that the compound favors El like conformations and can compete for ouabain binding to the Na/K-ATPase. Taken together, we have identified a new class of Na/K-ATPase ligand that may function as a CTS antagonist.
研究发现,ApoA-I与ABCA1是类似于一种受体-配体的相互作用来发挥其功能的。据此原理,我们建立了基于与ABCA1结合的ApoA-I的cell-ELISA-like的高通量筛选模型,对本实验室的合成和天然产物化合物库进行大规模筛选,以其发现调节ABCA1活性的化合物,为治疗抗动脉粥样硬化的新型先导化合物的出现奠定基础。
本研究采用trizol法提取MRC-5细胞总RNA,经逆转录合成cDNA。以此cDNA为模板,采用高保真的Prime Star DNA聚合酶和分段PCR的策略,进行限制性内切酶分析后,我们从其内部选择了xho I、EcoR I、Nhe I三个酶切位点,ABCA1 cDNA两端分别添加了sac I和salⅠ酶切位点,分段克隆了1823bp,1061 bp,2750 bp和1664bp的片段,与pMD-19T simple载体连接并测序正确后,酶切后与真核表达载体pIRES2-EGFP载体连接构建成功ABCA1 (cDNA全长6789bp)的真核表达载体。将构建成功的载体转入CHO细胞,以G418 500μg/ml的浓度筛选出稳定表达ABCA1的单克隆细胞,以此单克隆细胞包被96孔板,加入8μg/ml ApoA-Ⅰ为配基,孵育2小时后,依次加入anti-ApoA-I一抗和相应二抗,TMB显色,450nm测定OD值。
经各项条件优化后,建立起以ABCA1为靶标的cell-ELISA-like高通量筛选模型,以ABC家族抑制剂格列本脲为阳性药对模型进行评价,接着对本室2600个天然和合成化合物库进行了筛选,从中发现了一种氧杂葸酮(口山酮)类化合物№2026791具有明显的上调ABCA1活性的作用,其在50μM时上调活性达30%。流式细胞术和western-blot分析均证实了№2026791增加了细胞表面ApoA-I的结合,证实№2026791可能为上调ABCA1介导的脂质外流活性的激动剂。
本研究建立的ABCA1为靶标的cell-ELISA-like高通量新药筛选模型,可用来筛选对ABCA1脂质外流活性起调节作用的合成化合物及天然产物提取物,具有一定的创新性和广泛的实用性。筛选得到的阳性化合物№2026791经多种方法证实,具有潜在提高ABCA1脂质外流活性的能力,可为新型抗AS的先导化合物的发现创造了条件。
钠钾ATP酶(Na/K-ATPase),又称钠泵,是P型ATP酶的一员,存在于大多数动物细胞的细胞质膜中。早在1957年Skou等人发现其可作为ATP能量驱动的离子泵之后,它的离子转运功能及其相关的调节已得到深入的研究。虽然早期的研究表明此酶同样也在基因的表达和细胞的生长方面扮演重要角色,但直到近几年才发现其可以组装多种信号分子形成信号转导复合物,引发信号转导的级联反应,并借以对不同蛋白的功能进行调节。在质膜上它能够与Src结合形成二元受体并与小窝蛋白一起组装成信号转导复合物,借助Src激酶反式激活内皮生长因子受体EGFR,激活胞内信号转导的级联反应,参与细胞的生长和调控。研究钠钾ATP酶及其信号转导机制将有助于发现在肿瘤和心血管治疗方面找到新的药物靶点。
本研究采用密度梯度离心的方法,从猪肾中分离出了高纯度高活性的Na/K-ATPase蛋白。采用酶学的方法建立以Na/K-ATPase为靶点的高通量筛选模型,以测定其水解产生的Pi的量反映其活性的大小。以此模型对本室化合物库中2600个化合物进行了高通量筛选,共得到18个阳性化合物,均显示出对Na/K-ATPase有一定的抑制作用。其中6个具有相似结构,同属羟基口山酮类化合物。构效关系研究表明羟基的数目和位置对其活性至关重要。量效关系曲线表明,此类化合物不同于强心苷类代表药物乌本苷(ouabain),其对Na/K-ATPase呈现双相抑制作用,说明可能作用于Na/K-ATPase的两个不同构象。已经进行的实验研究发现,这一类化合物更易结合Na/K-ATPase的E1样构象,不同于ouabain的E2构象。并且这类化合物可以在一定程度拮抗ouabain与Na/K-ATPase的结合。显示了其作为强心苷类物质的潜在拮抗作用。
新发现的这类羟基口山酮类化合物作为Na/K-ATPase的新配体,将有助于研究Na/K-ATPase构象的变化和离子转运、信号转导等生理功能,有助于更好的理解Na/K-ATPase在机体中或细胞的正常生理活动中扮演的角色和重要作用。
Atherosclerosis is the principal pathogenesis for many critical cardiovascular diseases (e.g., coronary heart disease, angina pectoris, myocardial infarction and stroke).The characteristic component of the atherosclerotic plaque is the macrophage derived foam cell. Intracellular free cholesterol can be toxic to the cell and therefore an efficient cholesterol efflux mechanism in macrophage is mandatory to prevent cholesterol accumulation. The ATP-binding cassette transporter A1 (ABCA1), which belongs to a superfamily of ATP-binding cassette transporters (ABCs), mediates the rate-controlling step in the HDL particle formation and in the assembly of free cholesterol and phospholipids with lipid-poor apolipoprotein A-I (apoA-I). Several laboratories have demonstrated that lipid-poor apolipoprotein A-I (apoA-I) can interacts with ABCA1 to mediate cellular cholesterol and nascent HDL assembly, which suggests a possible receptor-ligand type interaction between ABCA1 and apoA-I. In the current study, a high-throughput assay cell-ELISA-like method for ABCA1 regulators targeted at the binding apoA-I was developed and used for screening a synthetic and natural compound library. The cell-ELISA based high throughput screen is conducted in a 96-well format using CHO cells stably transfected with ABCA1 pIRE2-EGFP expression vector and calibrated with reference ABCA1 inhibitor Glibenclamide. Among 2600 compounds,1 xanthone compound 2026791 was picked up as hits by the highthroughput screening assay, and the compound was further identified as potential accelerator of cholesterol efflux via ABCA1 by flow cytometry assay and western blot analysis.
Na,K-ATPase is an integral membrane protein found in most mammalian cells. It was initially discovered as an energy transducing ion pump that transports 3 Na+out and 2 K+ into the cell by hydrolysis of one molecule of ATP. The ligands of Digitalis-like glycosides have been reported to be the specific inhibitors of Na,K-ATPase which are most accessible to the E2-P form on the extracellular side, resulting in the specific inhibition of ATP hydrolysis and cation transport. Recently we and others have found that Na,K-ATPase can interact with Src to form a functional signaling compex which can be as the receptor of endogenous cardiotonic glycosides and mediate extracellular signal transduction into the cell so as to regulate cell growth and expression of various genes. In order to develop new promising chemicals targeted at Na,K-ATPase which benefit the cardiovascular diseases and cancer, A high throughput screen assay in a multiwell format was established. A library of 2600 compounds was screened using the developed assay, and a class of hydroxyxanthones with different inhibition of the Na,K-ATPase was identified. Further study of one compound MB5 indicate that the compound favors El like conformations and can compete for ouabain binding to the Na/K-ATPase. Taken together, we have identified a new class of Na/K-ATPase ligand that may function as a CTS antagonist.
引文
1. Murray, C. J., and Lopez, A. D. (1997) Lancet 349,1436-1442
2. Robins, S. J., Collins, D., Wittes, J. T., Papademetriou, V., Deedwania, P. C., Schaefer, E. J., McNamara, J. R., Kashyap, M. L., Hershman, J. M., Wexler, L. F., and Rubins, H. B. (2001) JAMA 285,1585-1591
3. Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M. B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., Wilt, T. J., and Wittes, J. (1999) N Engl J Med 341,410-418
4. Fielding, C. J., and Fielding, P. E. (1995) J Lipid Res 36,211-228
5. Oram, J. F., and Yokoyama, S. (1996) J Lipid Res 37,2473-2491
6. Brousseau, M. E., Eberhart, G. P., Dupuis, J., Asztalos, B. F., Goldkamp, A. L., Schaefer, E. J., and Freeman, M. W. (2000) J Lipid Res 41,1125-1135
7. Clee, S. M., Kastelein, J. J., van Dam, M., Marcil, M., Roomp, K., Zwarts, K. Y., Collins, J. A., Roelants, R., Tamasawa, N., Stulc, T., Suda, T., Ceska, R., Boucher, B., Rondeau, C., DeSouich, C., Brooks-Wilson, A., Molhuizen, H. O., Frohlich, J., Genest, J., Jr., and Hayden, M. R. (2000) J Clin Invest 106, 1263-1270
8. Oram, J. F., and Lawn, R. M. (2001) J Lipid Res 42,1173-1179
9. Remaley, A. T., Stonik, J. A., Demosky, S. J., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Eggerman, T. L., Patterson, A. P., Duverger, N. J., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2001) Biochem Biophys Res Commun 280,818-823
10. Schmitz, G., and Langmann, T. (2005) Biochim Biophys Acta 1735,1-19
11. Remaley, A. T., Thomas, F., Stonik, J. A., Demosky, S. J., Bark, S. E., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Patterson, A. P., Eggerman, T. L., Santamarina-Fojo, S., and Brewer, H. B. (2003) J Lipid Res 44,828-836
12. Witting, S. R., Maiorano, J. N., and Davidson, W. S. (2003) J Biol Chem 278, 40121-40127
13. Haidar, B., Denis, M., Marcil, M., Krimbou, L., and Genest, J., Jr. (2004) J Biol Chem 279,9963-9969
14. Nofer, J. R., Remaley, A. T., Feuerborn, R., Wolinnska, I., Engel, T., von Eckardstein, A., and Assmann, G. (2006) J Lipid Res 47,794-803
15. Tang, C., Vaughan, A. M., and Oram, J. F. (2004) J Biol Chem 279,7622-7628
16. Yamauchi, Y., Hayashi, M., Abe-Dohmae, S., and Yokoyama, S. (2003) J Biol Chem 278,47890-47897
17. Nieland, T. J., Chroni, A., Fitzgerald, M. L., Maliga, Z., Zannis, V. I., Kirchhausen, T., and Krieger, M. (2004) J Lipid Res 45,1256-1265
18. Wang, N., and Tall, A. R. (2003) Arterioscler Thromb Vasc Biol 23,1178-1184
19. Brewer, H. B., Jr., and Santamarina-Fojo, S. (2003) Am J Cardiol 91,3E-11E
20. Marcil, M., Bissonnette, R., Vincent, J., Krimbou, L., and Genest, J. (2003) Circulation 107,1366-1371
21. Chambenoit, O., Hamon, Y., Marguet, D., Rigneault, H., Rosseneu, M., and Chimini, G. (2001) J Biol Chem 276,9955-9960
22. Fitzgerald, M. L., Morris, A. L., Rhee, J. S., Andersson, L. P., Mendez, A. J., and Freeman, M. W. (2002) J Biol Chem 277,33178-33187
23. Panagotopulos, S. E., Witting, S. R., Horace, E. M., Hui, D. Y., Maiorano, J. N., and Davidson, W. S. (2002) J Biol Chem 277,39477-39484
24. Hamon, Y., Luciani, M. F., Becq, F., Verrier, B., Rubartelli, A., and Chimini, G. (1997) Blood 90,2911-2915
25. Becq, F., Hamon, Y., Bajetto, A., Gola, M., Verrier, B., and Chimini, G. (1997) J Biol Chem 272,2695-2699
26. Feng, B., and Tabas, I. (2002) J Biol Chem 277,43271-43280
27. Wang, N., Silver, D. L., Costet, P., and Tall, A. R. (2000) J Biol Chem 275, 33053-33058
28. Oram, J. F., Lawn, R. M., Garvin, M. R., and Wade, D. P. (2000) J Biol Chem 275,34508-34511
29. Von Eckardstein, A., Langer, C, Engel, T., Schaukal, I., Cignarella, A., Reinhardt, J., Lorkowski, S., Li, Z., Zhou, X., Cullen, P., and Assmann, G. (2001) FASEB J 15,1555-1561
30. Xiao, H. B., Sun, Z. L., Lu, X. Y., Li, D. Z., Xu, J. P., and Hu, Y. P. (2008) Can J Physiol Pharmacol 86,815-826
31. Muruganandan, S., Srinivasan, K., Gupta, S., Gupta, P. K., and Lal, J. (2005)J Ethnopharmacol 97,497-501
32. Gao, J., Xu, Y., Yang, Y., Zheng, Z., Jiang, W., Hong, B., Yan, X., and Si, S. (2008) J Biomol Screen 13,648-656
1. Michael Dean, Yannick Hamon, Giovann Chimini:The human ATP-binding cassette
(ABC)transporter superfamily. J Lipid Res 2001; 42:1007-1017.
2. Higgins CF:ABC transporters:from micro-organisms to man. Annu Rev Biol 1992; 8:67-113.
3. Dean MR. Allikmets:Evolution of ATP-binding cassette transporter genes. Curr Opin Gene 1995; 5:779-785.
4. Michael Dean, Yannick Hamon, Giovann Chimini:The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 2001; 42:1007-1017.
5. Knight BL:ATP-binding cassette transporter Al:regulation of cholesterol efflux. Biochem Soc Trans 2004; 32(1):124-127.
6. Jian Wang, John R. Burnett, Susan Near:Common and rare ABCA1 variants affecting plasma HDL cholesterol. Arterioscler Thromb Vasc Biol 2000; 20:1983-1989.
7. Xiaohui Zhao, Jacques Genest and Ruth McPherson:Endocytosis is enhanced in Tangier fibroblast. J Biol Chem 2001; 276(42):39476-39483.
8. Hovingh GK, Kuivenhoven JA and Bisoendial RJ:HDL deficiency and atherosclerosis:lessons from Tangier disease. J Intern Med 2004; 255(2):299-301.
9. John McNeish, Robert J.Aiello and Deborah Guyot:High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. PNAS 2000; 97(8):4245-4250.
10. Lawn RM, Wade DP, Couse TL, et al. ATP-binding cassette transporter 1 participates in LDL oxidation by artery wall cells. Arteroscler Thrimb Vasc Biol 2002;22(11):1877-1883.
11. Langmann T, Klucken J, Reil M, et al. Molecular cloning of the human ATP-binding cassette transporter 1(h ABCA1):evidence for sterol dependent regulation in macrophages.Biochem Biophys Res Commun 1999; 257(1):29-33.
12. Repa JJ, Berge KE, Pomajzl C, et al.Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors alpha and beta. J Biol Chem 2002; 277 (21):18793-18800.
13. Murthy S, Born E, Mathur SN, et al. LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells. J Lipid Res 2002; 43 (7):1054-1064.
14. Yu L, York J, Bergmann K, et al. J Biol Chem 2003; 278(18):15565-15570.
15. Yoshikawa T, Ide T, Shimano H:Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol
Endocrinol 2003; 17 (7):1240-1254.
16. Luo Y, Liang CP, Tall AR:The orphan nuclear receptor LRH-1potentiates the sterol-mediated induction of the human CETP gene by liver X receptor. J Biol Chem 2001; 276(27):24767-24773.
17. Schwart K, Lawn RM and Wade DP:ABC1 gene expression and ApoAl mediated cholesterol sterol efflux are regulated by LXR. Biochem Biophys Res Commun 2000; 274 (3):794-802.
18. Wade DP, Owen JS:Regulation of the cholesterol efflux gene ABCA1. Lancet 2001; 357(9251):161-163.
19. Huuskonen J, Vishnu M, Pullinger CR, et al. Regulation of ATP-binding cassette transporter A1 transcription by thyroid hormone receptor. Biochemistry 2004; 43 (6): 1626-1632.
20. Luo Y and Tall AR. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest 2000; 105 (4):513-520.
21. Oram JF, Lawn RM, Garvin MR, et al. ABCA1 is the camp inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem,2000, 275(44):34508-34511
22. Takahashi Y, Miyata M, Zheng P, et al. Identification of cAMP analogue inducible genes in RAW264 macrophages.Biochim Bio Phys Acta 2000; 1492 (2-3):385-389.
23. Feng B, Tabas I:ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages. Mechanism involves enhanced ABCA1 degradation in a process requiring full NPC1 activity. J Biol Chem 2002; 277 (45):43271-43280.
24. Khovidhunkit W, Moser AH, Shigenaga JK, et al. Endotoxin downregulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR. JLipid Res 2003; 44 (9):1728-36.
25. Castrillo A, Joseph SB, Vaidya SA, et al. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell 2003; 12 (4):805-816.
26. Kaplan R, Gan X, Menke JG, et al. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway. J Lipid Res 2002; 43 (6):952-959.
27. Panousis CG, Zuckeman SH. Interferon gamma induces down regulation of Tangier disease gene (ATP binding cassette transporter1) in macrophage derived foam cells. Arterosclerioscler Thromb Vase Biol 2000; 20 (6):1565-1571.
28. Ruan XZ, Moorhead JF, Fernando R, et al. PPAR Agonists Protect Mesangial Cells from Interleukin 1beta-Induced Intracellular Lipid Accumulation by Activating the ABCA1 Cholesterol Efflux Pathway. JAm Soc Nephrol 2003; 14(3):593-600.
29. Bungret S et al. J Biol Chem 2001; 276:23539-23546.
30. Wang J et al. Arteroscler Thrimb Vasc Biol 2002; 20:1983-1989.
31. Rigot V et al. J Lipid Res 2002;43:2077-2086.
32. Gao J et al. JBiomol Screen.2008 Aug;13(7):648-56. Epub 2008 Jul 1.
1. Murray, C. J., and Lopez, A. D. (1997) Lancet 349,1436-1442
2. Robins, S. J., Collins, D., Wittes, J. T., Papademetriou, V., Deedwania, P. C., Schaefer, E. J., McNamara, J. R., Kashyap, M. L., Hershman, J. M., Wexler, L. F., and Rubins, H. B. (2001) JAMA 285,1585-1591
3. Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M. B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., Wilt, T. J., and Wittes, J. (1999) N Engl J Med 341, 410-418
4. Fielding, C. J., and Fielding, P. E. (1995) J Lipid Res 36,211-228
5. Oram, J. F., and Yokoyama, S. (1996) JLipid Res 37,2473-2491
6. Brousseau, M. E., Eberhart, G. P., Dupuis, J., Asztalos, B. F., Goldkamp, A. L., Schaefer, E. J., and Freeman, M. W. (2000) J Lipid Res 41,1125-1135
7. Clee, S. M., Kastelein, J. J., van Dam, M., Marcil, M., Roomp, K., Zwarts, K. Y., Collins, J. A., Roelants, R., Tamasawa, N., Stulc, T., Suda, T., Ceska, R., Boucher, B., Rondeau, C., DeSouich, C, Brooks-Wilson, A., Molhuizen, H. O., Frohlich, J., Genest, J., Jr., and Hayden, M. R. (2000) J Clin Invest 106,1263-1270
8. Oram, J. F., and Lawn, R. M. (2001) J Lipid Res 42,1173-1179
9. Remaley, A. T., Stonik, J. A., Demosky, S. J., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Eggerman, T. L., Patterson, A. P., Duverger, N. J., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2001) Biochem Biophys Res Commun 280,818-823
10. Schmitz, G., and Langmann, T. (2005) Biochim Biophys Acta 1735,1-19
11. Remaley, A. T., Thomas, F., Stonik, J. A., Demosky, S. J., Bark, S. E., Neufeld, E. B., Bocharov, A. V, Vishnyakova, T. G., Patterson, A. P., Eggerman, T. L., Santamarina-Fojo, S., and Brewer, H. B. (2003) J Lipid Res 44,828-836
12. Witting, S. R., Maiorano, J. N., and Davidson, W. S. (2003) JBiol Chem 278,40121-40127
13. Haidar, B., Denis, M., Marcil, M., Krimbou, L., and Genest, J., Jr. (2004) J Biol Chem 279, 9963-9969
14. Nofer, J. R., Remaley, A. T., Feuerborn, R., Wolinnska, I., Engel, T., von Eckardstein, A., and Assmann, G. (2006) JLipid Res 47,794-803
15. Tang, C., Vaughan, A. M., and Oram, J. F. (2004) JBiol Chem 279,7622-7628
16. Yamauchi, Y., Hayashi, M., Abe-Dohmae, S., and Yokoyama, S. (2003) J Biol Chem 278, 47890-47897
17. Nieland, T. J., Chroni, A., Fitzgerald, M. L., Maliga, Z., Zannis, V. I., Kirchhausen, T., and Krieger, M. (2004) J Lipid Res 45,1256-1265
18. Wang,N., and Tall, A. R. (2003) Arterioscler Thromb Vasc Biol 23,1178-1184
19. Brewer, H. B., Jr., and Santamarina-Fojo, S. (2003) Am J Cardiol 91,3E-11E
20. Marcil, M., Bissonnette, R., Vincent, J., Krimbou, L., and Genest, J. (2003) Circulation 107, 1366-1371
21. Chambenoit, O., Hamon, Y., Marguet, D., Rigneault, H., Rosseneu, M., and Chimini, G. (2001) J Biol Chem 276,9955-9960
22. Fitzgerald, M. L., Morris, A. L., Rhee, J. S., Andersson, L. P., Mendez, A. J., and Freeman, M. W. (2002) J Biol Chem 277,33178-33187
23. Panagotopulos, S. E., Witting, S. R., Horace, E. M., Hui, D. Y., Maiorano, J. N., and Davidson, W. S. (2002) JBiol Chem 277,39477-39484
24. Hamon, Y., Luciani, M. F., Becq, F., Verrier, B., Rubartelli, A., and Chimini, G. (1997) Blood 90, 2911-2915
25. Becq, F., Hamon, Y., Bajetto, A., Gola, M., Verrier, B., and Chimini, G. (1997) J Biol Chem 272, 2695-2699
26. Feng, B., and Tabas, I. (2002) JBiol Chem 277,43271-43280
27. Wang, N., Silver, D. L., Costet, P., and Tall, A. R. (2000) JBiol Chem 275,33053-33058
28. Oram, J. F., Lawn, R. M., Garvin, M. R., and Wade, D. P. (2000) JBiol Chem 275,34508-34511
29. Von Eckardstein, A., Langer, C., Engel, T., Schaukal, I., Cignarella, A., Reinhardt, J., Lorkowski, S., Li, Z., Zhou, X., Cullen, P., and Assmann, G. (2001) FASEB J 15,1555-1561
30. Xiao, H. B., Sun, Z. L., Lu, X. Y, Li, D. Z., Xu, J. P., and Hu, Y P. (2008) Can J Physiol Pharmacol 86,815-826
31. Muruganandan, S., Srinivasan, K., Gupta, S., Gupta, P. K., and Lal, J. (2005) J Ethnopharmacol 97,497-501
32. Gao, J., Xu, Y, Yang, Y, Zheng, Z., Jiang, W., Hong, B., Yan, X., and Si, S. (2008) J Biomol Screen 13,648-656
33. Skou, J. C. (1957) Biochim Biophys Acta 23,394-401
34. Lingrel, J. B., and Kuntzweiler, T. (1994) JBiol Chem 269,19659-19662
35. Kaplan, J. H. (2002) Annu Rev Biochem 71,511-535
36. Xie, Z., and Askari, A. (2002) Eur JBiochem 269,2434-2439
37. Scheiner-Bobis, G. (2002) Eur J Biochem 269,2424-2433
38. Ringer, S. (1885) J Physiol 6,361-463 367
39. Schoner, W., and Scheiner-Bobis, G. (2005) Semin Nephrol 25,343-351
40. Peng, M., Huang, L., Xie, Z., Huang, W. H., and Askari, A. (1996) JBiol Chem 271,10372-10378
41. Haas, M., Wang, H., Tian, J., and Xie, Z. (2002) JBiol Chem 277,18694-18702
42. Yudowski, G. A., Efendiev, R., Pedemonte, C. H., and Bertorello, A. M. (2000) Proc Natl Acad Sci USA 97,6556-6561
43. Liu, J., Kesiry, R., Xie, Z., and Shapiro, J. I. (2004) Kidney Int 66,227-241
44. Liu, J., Periyasamy, S. M., Gunning, W., Fedorova,O. V., Bagrov, A. Y., Malhotra, D., Xie, Z., and Shapiro, J. I. (2002) Kidney Int 62,2118-2125
45. Liu, L., Gable, M. E., Garlid, K. D., and Askari, A. (2007) Mol Cell Biochem 306,231-237
46. Tian, J., Li, X., Liang, M., Liu, L., Xie, J. X., Ye, Q., Kometiani, P., Tillekeratne, M., Jin, R., and Xie, Z. (2009) J Biol Chem 284,14921-14929
1. Skou,J.C. The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim Biophys Acta.1957 Feb;23(2):394-401.
2. Scheiner-Bobis G. The sodium pump. Its molecular properties and mechanics of ion transport. Eur JBiochem.2002 May;269(10):2424-33
3. Ringer S. Regarding the influence of the Organic Constituents of the blood on the Contractility of the Ventricle. J Physiol.1885 Nov;6(6):361-463.7.
4. Schoner, W. and Scheiner-Bobis, G. Endogenous cardiac glycosides:hormones using the sodium pump as signal transducer. Semin. Nephrol.200525,343-351.
5. Contreras, R. G., Flores-Maldonado, C., Lazaro, A.,Shoshani, L., Flores-Benitez, D., Larre, I., and Cereijido,M. Ouabain binding to Na+,K+-ATPase relaxes cell attachment and sends a specific signal (NACos) to the nucleus. J. Membr. Biol.2004 198,147-158.
6. Peng, M., Huang, L., Xie, Z., Huang, W. H., and Askari, A. Partial inhibition of Na+,K+-ATPase by ouabain induces the Ca2+-dependent expressions of early-response genes in cardiac myocytes. J. Biol. Chem.1996 271,10372-10378.
7. Huang, L., Li, H., and Xie, Z. Ouabain-induced hypertrophy in cultured cardiac myocytes is accompanied by changes in expression of several late response genes.J. Mol. Cell Cardiol.1997 29,429-437.
8. Saunders, R. and Scheiner-Bobis, G. Ouabain stimulates endothelin release and expression in human endothelial cells without inhibiting the sodium pump. Eur. J. Biochem.2004 271,1054-1062.
9. Dmitrieva, R. I. and Doris, P. A. Ouabain is a potent promoter of growth and activator of ERK1/2 in ouabainresistant rat renal epithelial cells. J. Biol. Chem.2003 278,28160-28166.
10. Abramowitz, J., Dai, C., Hirschi, K. K., Dmitrieva, R. I., Doris, P. A., Liu, L., and Allen, J. C. (2003) Ouabain-and marinobufagin-induced proliferation of human umbilical vein smooth muscle cells and a rat vascular smooth muscle cell line, A7r5. Circulation 108,3048-3053.
11. Young, M. A., Gonfloni, S., Superti-Furga, G., Roux, B.,and Kuriyan, J. Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation. Cell 2001 105,115-126.
12. Xu, W., Harrison, S. C., and Eck, M. J. Three-dimensional structure of the tyrosine kinase c-Src. Nature 1997 385,595-602
13. Aydemir-Koksoy, A., Abramowitz, J., and Allen, J. C. Ouabain-induced signaling and vascular smooth muscle cell proliferation. J. Biol. Chem.2001 276, 46605-46611.
14. Haas, M., Wang, H., Tian, J., and Xie, Z. Src-mediated inter-receptor cross-talk between the Na+,K+-ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J. Biol. Chem.2002 277, 18694-18702.
15. Liu, J. Ouabain-induced endocytosis and signal transduction of the Na/K-ATPase. Front. Biosci.2005 10,2056-2063.
16. Yuan, Z., Cai, T., Tian, J., Ivanov, A. V., Giovannucci, D. R.,and Xie, Z. Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex. Mol.Biol. Cell 2005 16,4034-4045.
17. Tian, J., Cai, T., Yuan, Z., Wang, H., Liu, L., Haas, M., Maksimova, E., Huang, X. Y., and Xie, Z. J. (2006) Binding of Src to Na+,K+-ATPase Forms a functional signaling complex. Mol. Biol. Cell.17,317-326.
18. Ihle, J. N. The Janus kinase family and signaling through members of the cytokine receptor superfamily. Proc. Soc. Exp. Biol. Med.1994 206,268-272.
19. Wan, Y., Belt, A., Wang, Z., Voorhees, J., and Fisher, G. Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes. Int. J. Mol. Med.2001 7,329-334.
20. Ullrich, A. and Schlessinger, J. (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61,203-212.
21.Luttrell, L. M., Daaka, Y., and Lefkowitz, R. J. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr. Opin. Cell. Biol 1999 11,177-183.
22. Chen, K., Vita, J. A., Berk, B. C., and Keaney, Jr., J. F. c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation. J. Biol. Chem.2001 276, 16045-16050.
23. Andreev, J., Galisteo, M. L., Kranenburg, O., Logan, S. K., Chiu, E. S., Okigaki, M., Cary, L. A., Moolenaar, W. H., and Schlessinger, J. (2001) Src and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor receptor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J. Biol. Chem.276,20130-20135.
24. Prenzel, N., Fischer, O. M., Streit, S., Hart, S., and Ullrich, A. (2001) The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer 8,11-31.
25. Haas, M., Askari, A., and Xie, Z. (2000) Involvement of Src and epidermal growth factor receptor in the signal-transducing function of Na+,K+-ATPase. J. Biol. Chem. 275,27832-27837.
26. Rameh, L. E. and Cantley, L. C. The role of phosphoinositide 3-kinase lipid products in cell function. J.Biol. Chem.1999274,347-350.
27. Yudowski, G. A., Efendiev, R., Pedemonte, C. H., Katz, A. I., Berggren, P. O., Bertorello, A. M. Phosphoinositide-3 kinase binds to a proline-rich motif in the Na+,K+-ATPase alpha subunit and regulates its trafficking. Proc. Natl. Acad. Sci. USA.2000 97,6556-6561.
28. Barwe, S. P., Anilkumar, G., Moon, S. Y., Zheng, Y., Whitelegge, J. P., Rajasekaran, S. A., and Rajasekaran, A.K. Novel role for Na,K-ATPase in phosphatidyliphosphatidylinositol 3-kinase signaling and suppression of cell motility. Mol. Biol. Cell.2005 16,1082-1094.
29. Zhou, X., Jiang, G., Zhao, A., Bondeva, T., Hirszel, P., and Balla, T. (2001) Inhibition of Na,K-ATPase activates PI3 kinase and inhibits apoptosis in LLC-PK1 cells. Biochem.Biophys. Res. Commun.285,46-51.
30. Liu, J., Kesiry, R., Periyasami, S. M., Malhotra, D., Xie, Z., and Shapiro, J. (2004) Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a clathrin-dependent mechanism. Kidney Int.66,227-241.
31. Liu, J., Periyasamy, S. M., Gunning, W., Fedorova, O. V., Bagrov, A. Y., Malhotra, D., Xie, Z., and Shapiro, J. I. (2002) Effects of cardiac glycosides on sodium pump expression and function in LLC-PK1 and MDCK cells. Kidney Int.62,118-125.
32. Liu, P., Rudick, M., and Anderson, R. G. (2002) Multiple functions of caveolin-1. J. Biol. Chem.277,41295-41298.
33. Razani, B., Woodman, S. E., and Lisanti, M. P. (2002) Caveolae:from cell biology to animal physiology. Pharmacol. Rev.54,431-467.
34. Liu L,et al. Role of caveolae in signal-transducing function of cardiac Na+,K+-ATPase. Am J Physiol Cell Physiol.2003 Jun;284(6):C1550-60.
35. Wang H, et al. Ouabain assembles signaling cascades through the caveolar Na+,K+-ATPase. J Biol Chem.2004 Apr 23;279(17):17250-9
2. Robins, S. J., Collins, D., Wittes, J. T., Papademetriou, V., Deedwania, P. C., Schaefer, E. J., McNamara, J. R., Kashyap, M. L., Hershman, J. M., Wexler, L. F., and Rubins, H. B. (2001) JAMA 285,1585-1591
3. Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M. B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., Wilt, T. J., and Wittes, J. (1999) N Engl J Med 341,410-418
4. Fielding, C. J., and Fielding, P. E. (1995) J Lipid Res 36,211-228
5. Oram, J. F., and Yokoyama, S. (1996) J Lipid Res 37,2473-2491
6. Brousseau, M. E., Eberhart, G. P., Dupuis, J., Asztalos, B. F., Goldkamp, A. L., Schaefer, E. J., and Freeman, M. W. (2000) J Lipid Res 41,1125-1135
7. Clee, S. M., Kastelein, J. J., van Dam, M., Marcil, M., Roomp, K., Zwarts, K. Y., Collins, J. A., Roelants, R., Tamasawa, N., Stulc, T., Suda, T., Ceska, R., Boucher, B., Rondeau, C., DeSouich, C., Brooks-Wilson, A., Molhuizen, H. O., Frohlich, J., Genest, J., Jr., and Hayden, M. R. (2000) J Clin Invest 106, 1263-1270
8. Oram, J. F., and Lawn, R. M. (2001) J Lipid Res 42,1173-1179
9. Remaley, A. T., Stonik, J. A., Demosky, S. J., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Eggerman, T. L., Patterson, A. P., Duverger, N. J., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2001) Biochem Biophys Res Commun 280,818-823
10. Schmitz, G., and Langmann, T. (2005) Biochim Biophys Acta 1735,1-19
11. Remaley, A. T., Thomas, F., Stonik, J. A., Demosky, S. J., Bark, S. E., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Patterson, A. P., Eggerman, T. L., Santamarina-Fojo, S., and Brewer, H. B. (2003) J Lipid Res 44,828-836
12. Witting, S. R., Maiorano, J. N., and Davidson, W. S. (2003) J Biol Chem 278, 40121-40127
13. Haidar, B., Denis, M., Marcil, M., Krimbou, L., and Genest, J., Jr. (2004) J Biol Chem 279,9963-9969
14. Nofer, J. R., Remaley, A. T., Feuerborn, R., Wolinnska, I., Engel, T., von Eckardstein, A., and Assmann, G. (2006) J Lipid Res 47,794-803
15. Tang, C., Vaughan, A. M., and Oram, J. F. (2004) J Biol Chem 279,7622-7628
16. Yamauchi, Y., Hayashi, M., Abe-Dohmae, S., and Yokoyama, S. (2003) J Biol Chem 278,47890-47897
17. Nieland, T. J., Chroni, A., Fitzgerald, M. L., Maliga, Z., Zannis, V. I., Kirchhausen, T., and Krieger, M. (2004) J Lipid Res 45,1256-1265
18. Wang, N., and Tall, A. R. (2003) Arterioscler Thromb Vasc Biol 23,1178-1184
19. Brewer, H. B., Jr., and Santamarina-Fojo, S. (2003) Am J Cardiol 91,3E-11E
20. Marcil, M., Bissonnette, R., Vincent, J., Krimbou, L., and Genest, J. (2003) Circulation 107,1366-1371
21. Chambenoit, O., Hamon, Y., Marguet, D., Rigneault, H., Rosseneu, M., and Chimini, G. (2001) J Biol Chem 276,9955-9960
22. Fitzgerald, M. L., Morris, A. L., Rhee, J. S., Andersson, L. P., Mendez, A. J., and Freeman, M. W. (2002) J Biol Chem 277,33178-33187
23. Panagotopulos, S. E., Witting, S. R., Horace, E. M., Hui, D. Y., Maiorano, J. N., and Davidson, W. S. (2002) J Biol Chem 277,39477-39484
24. Hamon, Y., Luciani, M. F., Becq, F., Verrier, B., Rubartelli, A., and Chimini, G. (1997) Blood 90,2911-2915
25. Becq, F., Hamon, Y., Bajetto, A., Gola, M., Verrier, B., and Chimini, G. (1997) J Biol Chem 272,2695-2699
26. Feng, B., and Tabas, I. (2002) J Biol Chem 277,43271-43280
27. Wang, N., Silver, D. L., Costet, P., and Tall, A. R. (2000) J Biol Chem 275, 33053-33058
28. Oram, J. F., Lawn, R. M., Garvin, M. R., and Wade, D. P. (2000) J Biol Chem 275,34508-34511
29. Von Eckardstein, A., Langer, C, Engel, T., Schaukal, I., Cignarella, A., Reinhardt, J., Lorkowski, S., Li, Z., Zhou, X., Cullen, P., and Assmann, G. (2001) FASEB J 15,1555-1561
30. Xiao, H. B., Sun, Z. L., Lu, X. Y., Li, D. Z., Xu, J. P., and Hu, Y. P. (2008) Can J Physiol Pharmacol 86,815-826
31. Muruganandan, S., Srinivasan, K., Gupta, S., Gupta, P. K., and Lal, J. (2005)J Ethnopharmacol 97,497-501
32. Gao, J., Xu, Y., Yang, Y., Zheng, Z., Jiang, W., Hong, B., Yan, X., and Si, S. (2008) J Biomol Screen 13,648-656
1. Michael Dean, Yannick Hamon, Giovann Chimini:The human ATP-binding cassette
(ABC)transporter superfamily. J Lipid Res 2001; 42:1007-1017.
2. Higgins CF:ABC transporters:from micro-organisms to man. Annu Rev Biol 1992; 8:67-113.
3. Dean MR. Allikmets:Evolution of ATP-binding cassette transporter genes. Curr Opin Gene 1995; 5:779-785.
4. Michael Dean, Yannick Hamon, Giovann Chimini:The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 2001; 42:1007-1017.
5. Knight BL:ATP-binding cassette transporter Al:regulation of cholesterol efflux. Biochem Soc Trans 2004; 32(1):124-127.
6. Jian Wang, John R. Burnett, Susan Near:Common and rare ABCA1 variants affecting plasma HDL cholesterol. Arterioscler Thromb Vasc Biol 2000; 20:1983-1989.
7. Xiaohui Zhao, Jacques Genest and Ruth McPherson:Endocytosis is enhanced in Tangier fibroblast. J Biol Chem 2001; 276(42):39476-39483.
8. Hovingh GK, Kuivenhoven JA and Bisoendial RJ:HDL deficiency and atherosclerosis:lessons from Tangier disease. J Intern Med 2004; 255(2):299-301.
9. John McNeish, Robert J.Aiello and Deborah Guyot:High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. PNAS 2000; 97(8):4245-4250.
10. Lawn RM, Wade DP, Couse TL, et al. ATP-binding cassette transporter 1 participates in LDL oxidation by artery wall cells. Arteroscler Thrimb Vasc Biol 2002;22(11):1877-1883.
11. Langmann T, Klucken J, Reil M, et al. Molecular cloning of the human ATP-binding cassette transporter 1(h ABCA1):evidence for sterol dependent regulation in macrophages.Biochem Biophys Res Commun 1999; 257(1):29-33.
12. Repa JJ, Berge KE, Pomajzl C, et al.Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors alpha and beta. J Biol Chem 2002; 277 (21):18793-18800.
13. Murthy S, Born E, Mathur SN, et al. LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells. J Lipid Res 2002; 43 (7):1054-1064.
14. Yu L, York J, Bergmann K, et al. J Biol Chem 2003; 278(18):15565-15570.
15. Yoshikawa T, Ide T, Shimano H:Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol
Endocrinol 2003; 17 (7):1240-1254.
16. Luo Y, Liang CP, Tall AR:The orphan nuclear receptor LRH-1potentiates the sterol-mediated induction of the human CETP gene by liver X receptor. J Biol Chem 2001; 276(27):24767-24773.
17. Schwart K, Lawn RM and Wade DP:ABC1 gene expression and ApoAl mediated cholesterol sterol efflux are regulated by LXR. Biochem Biophys Res Commun 2000; 274 (3):794-802.
18. Wade DP, Owen JS:Regulation of the cholesterol efflux gene ABCA1. Lancet 2001; 357(9251):161-163.
19. Huuskonen J, Vishnu M, Pullinger CR, et al. Regulation of ATP-binding cassette transporter A1 transcription by thyroid hormone receptor. Biochemistry 2004; 43 (6): 1626-1632.
20. Luo Y and Tall AR. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest 2000; 105 (4):513-520.
21. Oram JF, Lawn RM, Garvin MR, et al. ABCA1 is the camp inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages. J Biol Chem,2000, 275(44):34508-34511
22. Takahashi Y, Miyata M, Zheng P, et al. Identification of cAMP analogue inducible genes in RAW264 macrophages.Biochim Bio Phys Acta 2000; 1492 (2-3):385-389.
23. Feng B, Tabas I:ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages. Mechanism involves enhanced ABCA1 degradation in a process requiring full NPC1 activity. J Biol Chem 2002; 277 (45):43271-43280.
24. Khovidhunkit W, Moser AH, Shigenaga JK, et al. Endotoxin downregulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR. JLipid Res 2003; 44 (9):1728-36.
25. Castrillo A, Joseph SB, Vaidya SA, et al. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell 2003; 12 (4):805-816.
26. Kaplan R, Gan X, Menke JG, et al. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway. J Lipid Res 2002; 43 (6):952-959.
27. Panousis CG, Zuckeman SH. Interferon gamma induces down regulation of Tangier disease gene (ATP binding cassette transporter1) in macrophage derived foam cells. Arterosclerioscler Thromb Vase Biol 2000; 20 (6):1565-1571.
28. Ruan XZ, Moorhead JF, Fernando R, et al. PPAR Agonists Protect Mesangial Cells from Interleukin 1beta-Induced Intracellular Lipid Accumulation by Activating the ABCA1 Cholesterol Efflux Pathway. JAm Soc Nephrol 2003; 14(3):593-600.
29. Bungret S et al. J Biol Chem 2001; 276:23539-23546.
30. Wang J et al. Arteroscler Thrimb Vasc Biol 2002; 20:1983-1989.
31. Rigot V et al. J Lipid Res 2002;43:2077-2086.
32. Gao J et al. JBiomol Screen.2008 Aug;13(7):648-56. Epub 2008 Jul 1.
1. Murray, C. J., and Lopez, A. D. (1997) Lancet 349,1436-1442
2. Robins, S. J., Collins, D., Wittes, J. T., Papademetriou, V., Deedwania, P. C., Schaefer, E. J., McNamara, J. R., Kashyap, M. L., Hershman, J. M., Wexler, L. F., and Rubins, H. B. (2001) JAMA 285,1585-1591
3. Rubins, H. B., Robins, S. J., Collins, D., Fye, C. L., Anderson, J. W., Elam, M. B., Faas, F. H., Linares, E., Schaefer, E. J., Schectman, G., Wilt, T. J., and Wittes, J. (1999) N Engl J Med 341, 410-418
4. Fielding, C. J., and Fielding, P. E. (1995) J Lipid Res 36,211-228
5. Oram, J. F., and Yokoyama, S. (1996) JLipid Res 37,2473-2491
6. Brousseau, M. E., Eberhart, G. P., Dupuis, J., Asztalos, B. F., Goldkamp, A. L., Schaefer, E. J., and Freeman, M. W. (2000) J Lipid Res 41,1125-1135
7. Clee, S. M., Kastelein, J. J., van Dam, M., Marcil, M., Roomp, K., Zwarts, K. Y., Collins, J. A., Roelants, R., Tamasawa, N., Stulc, T., Suda, T., Ceska, R., Boucher, B., Rondeau, C., DeSouich, C, Brooks-Wilson, A., Molhuizen, H. O., Frohlich, J., Genest, J., Jr., and Hayden, M. R. (2000) J Clin Invest 106,1263-1270
8. Oram, J. F., and Lawn, R. M. (2001) J Lipid Res 42,1173-1179
9. Remaley, A. T., Stonik, J. A., Demosky, S. J., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Eggerman, T. L., Patterson, A. P., Duverger, N. J., Santamarina-Fojo, S., and Brewer, H. B., Jr. (2001) Biochem Biophys Res Commun 280,818-823
10. Schmitz, G., and Langmann, T. (2005) Biochim Biophys Acta 1735,1-19
11. Remaley, A. T., Thomas, F., Stonik, J. A., Demosky, S. J., Bark, S. E., Neufeld, E. B., Bocharov, A. V, Vishnyakova, T. G., Patterson, A. P., Eggerman, T. L., Santamarina-Fojo, S., and Brewer, H. B. (2003) J Lipid Res 44,828-836
12. Witting, S. R., Maiorano, J. N., and Davidson, W. S. (2003) JBiol Chem 278,40121-40127
13. Haidar, B., Denis, M., Marcil, M., Krimbou, L., and Genest, J., Jr. (2004) J Biol Chem 279, 9963-9969
14. Nofer, J. R., Remaley, A. T., Feuerborn, R., Wolinnska, I., Engel, T., von Eckardstein, A., and Assmann, G. (2006) JLipid Res 47,794-803
15. Tang, C., Vaughan, A. M., and Oram, J. F. (2004) JBiol Chem 279,7622-7628
16. Yamauchi, Y., Hayashi, M., Abe-Dohmae, S., and Yokoyama, S. (2003) J Biol Chem 278, 47890-47897
17. Nieland, T. J., Chroni, A., Fitzgerald, M. L., Maliga, Z., Zannis, V. I., Kirchhausen, T., and Krieger, M. (2004) J Lipid Res 45,1256-1265
18. Wang,N., and Tall, A. R. (2003) Arterioscler Thromb Vasc Biol 23,1178-1184
19. Brewer, H. B., Jr., and Santamarina-Fojo, S. (2003) Am J Cardiol 91,3E-11E
20. Marcil, M., Bissonnette, R., Vincent, J., Krimbou, L., and Genest, J. (2003) Circulation 107, 1366-1371
21. Chambenoit, O., Hamon, Y., Marguet, D., Rigneault, H., Rosseneu, M., and Chimini, G. (2001) J Biol Chem 276,9955-9960
22. Fitzgerald, M. L., Morris, A. L., Rhee, J. S., Andersson, L. P., Mendez, A. J., and Freeman, M. W. (2002) J Biol Chem 277,33178-33187
23. Panagotopulos, S. E., Witting, S. R., Horace, E. M., Hui, D. Y., Maiorano, J. N., and Davidson, W. S. (2002) JBiol Chem 277,39477-39484
24. Hamon, Y., Luciani, M. F., Becq, F., Verrier, B., Rubartelli, A., and Chimini, G. (1997) Blood 90, 2911-2915
25. Becq, F., Hamon, Y., Bajetto, A., Gola, M., Verrier, B., and Chimini, G. (1997) J Biol Chem 272, 2695-2699
26. Feng, B., and Tabas, I. (2002) JBiol Chem 277,43271-43280
27. Wang, N., Silver, D. L., Costet, P., and Tall, A. R. (2000) JBiol Chem 275,33053-33058
28. Oram, J. F., Lawn, R. M., Garvin, M. R., and Wade, D. P. (2000) JBiol Chem 275,34508-34511
29. Von Eckardstein, A., Langer, C., Engel, T., Schaukal, I., Cignarella, A., Reinhardt, J., Lorkowski, S., Li, Z., Zhou, X., Cullen, P., and Assmann, G. (2001) FASEB J 15,1555-1561
30. Xiao, H. B., Sun, Z. L., Lu, X. Y, Li, D. Z., Xu, J. P., and Hu, Y P. (2008) Can J Physiol Pharmacol 86,815-826
31. Muruganandan, S., Srinivasan, K., Gupta, S., Gupta, P. K., and Lal, J. (2005) J Ethnopharmacol 97,497-501
32. Gao, J., Xu, Y, Yang, Y, Zheng, Z., Jiang, W., Hong, B., Yan, X., and Si, S. (2008) J Biomol Screen 13,648-656
33. Skou, J. C. (1957) Biochim Biophys Acta 23,394-401
34. Lingrel, J. B., and Kuntzweiler, T. (1994) JBiol Chem 269,19659-19662
35. Kaplan, J. H. (2002) Annu Rev Biochem 71,511-535
36. Xie, Z., and Askari, A. (2002) Eur JBiochem 269,2434-2439
37. Scheiner-Bobis, G. (2002) Eur J Biochem 269,2424-2433
38. Ringer, S. (1885) J Physiol 6,361-463 367
39. Schoner, W., and Scheiner-Bobis, G. (2005) Semin Nephrol 25,343-351
40. Peng, M., Huang, L., Xie, Z., Huang, W. H., and Askari, A. (1996) JBiol Chem 271,10372-10378
41. Haas, M., Wang, H., Tian, J., and Xie, Z. (2002) JBiol Chem 277,18694-18702
42. Yudowski, G. A., Efendiev, R., Pedemonte, C. H., and Bertorello, A. M. (2000) Proc Natl Acad Sci USA 97,6556-6561
43. Liu, J., Kesiry, R., Xie, Z., and Shapiro, J. I. (2004) Kidney Int 66,227-241
44. Liu, J., Periyasamy, S. M., Gunning, W., Fedorova,O. V., Bagrov, A. Y., Malhotra, D., Xie, Z., and Shapiro, J. I. (2002) Kidney Int 62,2118-2125
45. Liu, L., Gable, M. E., Garlid, K. D., and Askari, A. (2007) Mol Cell Biochem 306,231-237
46. Tian, J., Li, X., Liang, M., Liu, L., Xie, J. X., Ye, Q., Kometiani, P., Tillekeratne, M., Jin, R., and Xie, Z. (2009) J Biol Chem 284,14921-14929
1. Skou,J.C. The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochim Biophys Acta.1957 Feb;23(2):394-401.
2. Scheiner-Bobis G. The sodium pump. Its molecular properties and mechanics of ion transport. Eur JBiochem.2002 May;269(10):2424-33
3. Ringer S. Regarding the influence of the Organic Constituents of the blood on the Contractility of the Ventricle. J Physiol.1885 Nov;6(6):361-463.7.
4. Schoner, W. and Scheiner-Bobis, G. Endogenous cardiac glycosides:hormones using the sodium pump as signal transducer. Semin. Nephrol.200525,343-351.
5. Contreras, R. G., Flores-Maldonado, C., Lazaro, A.,Shoshani, L., Flores-Benitez, D., Larre, I., and Cereijido,M. Ouabain binding to Na+,K+-ATPase relaxes cell attachment and sends a specific signal (NACos) to the nucleus. J. Membr. Biol.2004 198,147-158.
6. Peng, M., Huang, L., Xie, Z., Huang, W. H., and Askari, A. Partial inhibition of Na+,K+-ATPase by ouabain induces the Ca2+-dependent expressions of early-response genes in cardiac myocytes. J. Biol. Chem.1996 271,10372-10378.
7. Huang, L., Li, H., and Xie, Z. Ouabain-induced hypertrophy in cultured cardiac myocytes is accompanied by changes in expression of several late response genes.J. Mol. Cell Cardiol.1997 29,429-437.
8. Saunders, R. and Scheiner-Bobis, G. Ouabain stimulates endothelin release and expression in human endothelial cells without inhibiting the sodium pump. Eur. J. Biochem.2004 271,1054-1062.
9. Dmitrieva, R. I. and Doris, P. A. Ouabain is a potent promoter of growth and activator of ERK1/2 in ouabainresistant rat renal epithelial cells. J. Biol. Chem.2003 278,28160-28166.
10. Abramowitz, J., Dai, C., Hirschi, K. K., Dmitrieva, R. I., Doris, P. A., Liu, L., and Allen, J. C. (2003) Ouabain-and marinobufagin-induced proliferation of human umbilical vein smooth muscle cells and a rat vascular smooth muscle cell line, A7r5. Circulation 108,3048-3053.
11. Young, M. A., Gonfloni, S., Superti-Furga, G., Roux, B.,and Kuriyan, J. Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation. Cell 2001 105,115-126.
12. Xu, W., Harrison, S. C., and Eck, M. J. Three-dimensional structure of the tyrosine kinase c-Src. Nature 1997 385,595-602
13. Aydemir-Koksoy, A., Abramowitz, J., and Allen, J. C. Ouabain-induced signaling and vascular smooth muscle cell proliferation. J. Biol. Chem.2001 276, 46605-46611.
14. Haas, M., Wang, H., Tian, J., and Xie, Z. Src-mediated inter-receptor cross-talk between the Na+,K+-ATPase and the epidermal growth factor receptor relays the signal from ouabain to mitogen-activated protein kinases. J. Biol. Chem.2002 277, 18694-18702.
15. Liu, J. Ouabain-induced endocytosis and signal transduction of the Na/K-ATPase. Front. Biosci.2005 10,2056-2063.
16. Yuan, Z., Cai, T., Tian, J., Ivanov, A. V., Giovannucci, D. R.,and Xie, Z. Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex. Mol.Biol. Cell 2005 16,4034-4045.
17. Tian, J., Cai, T., Yuan, Z., Wang, H., Liu, L., Haas, M., Maksimova, E., Huang, X. Y., and Xie, Z. J. (2006) Binding of Src to Na+,K+-ATPase Forms a functional signaling complex. Mol. Biol. Cell.17,317-326.
18. Ihle, J. N. The Janus kinase family and signaling through members of the cytokine receptor superfamily. Proc. Soc. Exp. Biol. Med.1994 206,268-272.
19. Wan, Y., Belt, A., Wang, Z., Voorhees, J., and Fisher, G. Transmodulation of epidermal growth factor receptor mediates IL-1 beta-induced MMP-1 expression in cultured human keratinocytes. Int. J. Mol. Med.2001 7,329-334.
20. Ullrich, A. and Schlessinger, J. (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61,203-212.
21.Luttrell, L. M., Daaka, Y., and Lefkowitz, R. J. Regulation of tyrosine kinase cascades by G-protein-coupled receptors. Curr. Opin. Cell. Biol 1999 11,177-183.
22. Chen, K., Vita, J. A., Berk, B. C., and Keaney, Jr., J. F. c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation. J. Biol. Chem.2001 276, 16045-16050.
23. Andreev, J., Galisteo, M. L., Kranenburg, O., Logan, S. K., Chiu, E. S., Okigaki, M., Cary, L. A., Moolenaar, W. H., and Schlessinger, J. (2001) Src and Pyk2 mediate G-protein-coupled receptor activation of epidermal growth factor receptor (EGFR) but are not required for coupling to the mitogen-activated protein (MAP) kinase signaling cascade. J. Biol. Chem.276,20130-20135.
24. Prenzel, N., Fischer, O. M., Streit, S., Hart, S., and Ullrich, A. (2001) The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer 8,11-31.
25. Haas, M., Askari, A., and Xie, Z. (2000) Involvement of Src and epidermal growth factor receptor in the signal-transducing function of Na+,K+-ATPase. J. Biol. Chem. 275,27832-27837.
26. Rameh, L. E. and Cantley, L. C. The role of phosphoinositide 3-kinase lipid products in cell function. J.Biol. Chem.1999274,347-350.
27. Yudowski, G. A., Efendiev, R., Pedemonte, C. H., Katz, A. I., Berggren, P. O., Bertorello, A. M. Phosphoinositide-3 kinase binds to a proline-rich motif in the Na+,K+-ATPase alpha subunit and regulates its trafficking. Proc. Natl. Acad. Sci. USA.2000 97,6556-6561.
28. Barwe, S. P., Anilkumar, G., Moon, S. Y., Zheng, Y., Whitelegge, J. P., Rajasekaran, S. A., and Rajasekaran, A.K. Novel role for Na,K-ATPase in phosphatidyliphosphatidylinositol 3-kinase signaling and suppression of cell motility. Mol. Biol. Cell.2005 16,1082-1094.
29. Zhou, X., Jiang, G., Zhao, A., Bondeva, T., Hirszel, P., and Balla, T. (2001) Inhibition of Na,K-ATPase activates PI3 kinase and inhibits apoptosis in LLC-PK1 cells. Biochem.Biophys. Res. Commun.285,46-51.
30. Liu, J., Kesiry, R., Periyasami, S. M., Malhotra, D., Xie, Z., and Shapiro, J. (2004) Ouabain induces endocytosis of plasmalemmal Na/K-ATPase in LLC-PK1 cells by a clathrin-dependent mechanism. Kidney Int.66,227-241.
31. Liu, J., Periyasamy, S. M., Gunning, W., Fedorova, O. V., Bagrov, A. Y., Malhotra, D., Xie, Z., and Shapiro, J. I. (2002) Effects of cardiac glycosides on sodium pump expression and function in LLC-PK1 and MDCK cells. Kidney Int.62,118-125.
32. Liu, P., Rudick, M., and Anderson, R. G. (2002) Multiple functions of caveolin-1. J. Biol. Chem.277,41295-41298.
33. Razani, B., Woodman, S. E., and Lisanti, M. P. (2002) Caveolae:from cell biology to animal physiology. Pharmacol. Rev.54,431-467.
34. Liu L,et al. Role of caveolae in signal-transducing function of cardiac Na+,K+-ATPase. Am J Physiol Cell Physiol.2003 Jun;284(6):C1550-60.
35. Wang H, et al. Ouabain assembles signaling cascades through the caveolar Na+,K+-ATPase. J Biol Chem.2004 Apr 23;279(17):17250-9