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首页> 外文学位 >Molecular mechanisms involved in adenosine receptor mediated suppression of foam cell formation: A2A adenosine receptor activation decreases foam cell formation by enhancing ABCA1 and 27-hydroxylase dependent cholesterol efflux.
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Molecular mechanisms involved in adenosine receptor mediated suppression of foam cell formation: A2A adenosine receptor activation decreases foam cell formation by enhancing ABCA1 and 27-hydroxylase dependent cholesterol efflux.

机译：参与腺苷受体介导的泡沫细胞形成抑制的分子机制：A2A腺苷受体激活通过增强ABCA1和27-羟化酶依赖性胆固醇外排而减少泡沫细胞形成。

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摘要

Immune and inflammatory cells play a critical role in the pathogenesis of atherosclerotic plaques. Accumulation of foam cells, lipid-laden monocytes, is one of the earliest markers of plaque formation. We have demonstrated that adenosine A2A receptors inhibit foam cell formation and stimulate production of ABCA1, the primary transporter of lipoproteins and stimulate production of 27-hydroxylase, an enzyme involved in the conversion of cholesterol. We therefore asked whether the effects of adenosine A2A receptors on foam cell formation in vitro are mediated by proteins involved in reverse cholesterol transport, ABCA1, ABCG1, apoE or 27-hydroxylase. The adenosine A2A receptor agonist CGS21680 (1muM) increases expression of ABCA1 (by 20+/-5%, n=4) and inhibits Interferon-gamma-stimulated foam cell formation (59+/-6% inhibition, p0.004 vs. IFNgamma alone, n=3) in THP-1 cells, a human monocytoid cell line. Specific lentiviral siRNA infection markedly reduces ABCA1, ABCG1, apoE or 27-hydroxylase mRNA in THP-1 cells. Despite diminished ABCG1 expression (81+/-5% inhibition, p0.0001 vs. IFNgamma alone, n=3), and diminished apoE expression (p0.0002, IFNgamma CGS vs. IFNgamma alone, n=4) CGS-21680 inhibits foam cell formation. CGS-21680 has no effect on foam cell formation in ABCA1 knockdown cells (5+/-3% inhibition p0.85 vs. IFNgamma alone, n=3) or in 27-hydroxylase knockdown cells (4+/-2% p0.5113 inhibition vs. IFNgamma alone n=4).;The A2A agonist CGS-21680 increases apoAI-mediated cholesterol efflux nearly 2-fold in wildtype macrophages (from 9.5% to 17.5+/-2.5% [3H] cholesterol efflux, p0.0090 vs. control, n=3) but not in ABCA1 KD cells or 27-hydroxylase knockdown cells.;Activation of Epac, a signaling molecule downstream of the A2A receptor, increased ABCA1 (23+/-5%, p0.0007 vs. control, n=3) and Phospho-ABCA1 (13+/-5% p0.0003 vs. control, n=3) protein levels. These results demonstrate that adenosine A2A receptor occupancy diminishes foam cell formation by increasing expression and function of ABCA1 and 27-hydroxylase.
机译：免疫细胞和炎性细胞在动脉粥样硬化斑块的发病机理中起关键作用。富含脂质的单核细胞泡沫细胞的积累是斑块形成的最早标志之一。我们已经证明，腺苷A2A受体抑制泡沫细胞形成并刺激ABCA1（脂蛋白的主要转运蛋白）的产生并刺激27-羟化酶（一种参与胆固醇转化的酶）的产生。因此，我们问腺苷A2A受体对体外泡沫细胞形成的影响是否由参与反向胆固醇转运的蛋白，ABCA1，ABCG1，apoE或27-羟化酶介导。腺苷A2A受体激动剂CGS21680（1μM）增加ABCA1的表达（增加20 +/- 5％，n = 4）并抑制干扰素-γ刺激的泡沫细胞形成（抑制59 +/- 6％，相对于p <0.004）。在THP-1细胞（人类单核细胞系）中仅存在IFNγ，n = 3）。特定的慢病毒siRNA感染可显着降低THP-1细胞中的ABCA1，ABCG1，apoE或27-羟化酶mRNA。尽管ABCG1表达减少（81 +/- 5％抑制，p <0.0001 vs.单独IFNgamma，n = 3）和apoE表达减少（p <0.0002，IFNgamma CGS vs.单独IFNgamma，n = 4）CGS-21680抑制泡沫细胞的形成。 CGS-21680对ABCA1敲除细胞中泡沫细胞的形成没有影响（5 +/- 3％抑制作用p <0.85，而单独的IFNgamma，n = 3）或在27-羟化酶敲除细胞中（4 +/- 2％p <与单独的IFNγ相比，抑制作用为0.5113，n = 4）。； A2A激动剂CGS-21680在野生型巨噬细胞中使apoAI介导的胆固醇外流增加近2倍（从9.5％增至17.5 +/- 2.5％[3H]胆固醇外流，p <与对照组相比为0.0090，n = 3），但在ABCA1 KD细胞或27-羟化酶敲低细胞中则没有。;激活A2A受体下游的信号分子Epac会增加ABCA1（23 +/- 5％，p <0.0007 vs.对照，n ＝ 3）和磷酸-ABCA1（相对于对照，n ＝ 3，13 +/- 5％p ＜0.0003）蛋白质水平。这些结果表明，腺苷A2A受体的存在通过增加ABCA1和27-羟化酶的表达和功能来减少泡沫细胞的形成。

著录项

  • 作者

    Bingham, Taiese Crystal.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Biology Molecular.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 155 p.
  • 总页数 155
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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