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首页> 外文学位 >Cytoskeletal associations of SAPK/MAPK members, and a role for PKG and phosphatase(s) in heparin modulation of inflammation-induced signal transduction, in endothelial cells.
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Cytoskeletal associations of SAPK/MAPK members, and a role for PKG and phosphatase(s) in heparin modulation of inflammation-induced signal transduction, in endothelial cells.

机译：内皮细胞中SAPK / MAPK成员的细胞骨架关联以及PKG和磷酸酶在肝素调节炎症诱导的信号转导中的作用。

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摘要

The initial stages of atherosclerosis involve the chronic activation of the endothelium. Endothelium activation results due to stimulation by an array of inflammatory signals such as cytokines like TNF-alpha and reactive oxygen species like hydrogen peroxide, in part generated by circulating immune cells. The endothelial cells themselves, once activated, initiate cytoplasmic signal transduction pathways, such as the classic MAPK and SAPK pathways, that result in the up-regulation of the genes of some of these inflammatory signals such as TNF-alpha and IL-6. The glycosaminoglycan heparin is antiproliferative towards smooth muscle cell growth. Heparin treatment of endothelial cells activated with the cytokine TNF-alpha caused a reduction, at the molecular level, in the activities of the SAPKs JNK and p38. This modulatory effect could be observed at least one step upstream, in particular the MAPKK MEK3 that activates p38 in response to TNF-alpha. The downstream effects of heparin were monitored as well. Heparin was able to attenuate the phosphorylation of the transcription factor c-Jun, a JNK substrate. Heparin also caused a decrease in stress fiber formation induced by TNF-alpha, an effect that is regulated by the p38/MAPKAPK-2/HSP27 pathway. Heparin's attenuation of SAPK activation was reversed by a tyrosine phosphatase inhibitor, sodium orthovanadate, and further experiments revealed that heparin increased the DSP MKP-1 in a concentration- and time-dependent manner. In addition, heparin's effect on the SAPK pathway was found to be sensitive to a cGK inhibitor, signifying a role for the cGMP/cGK pathway in heparin's regulation of SAPK pathways. Heparin receptor antibodies were able to mimic heparin by reducing TNF-alpha-induced SAPK activation as well. Together these indicate that heparin is anti-inflammatory and anti-oxidant towards activated endothelial cells. Finally, the cytoskeletal association of members of the SAPK and MAPK pathways was studied. The results indicated that the phosphorylated forms of the SAM and MAPK associated with cytoskeletal elements, and that their MAPKKs are predominantly found in the nuclei with the exception of pMEK7. The MAPKKK MEKK1 and scaffold protein HP-1, two proteins that regulate JNK activity, were also found associated with stress fibers.
机译：动脉粥样硬化的初始阶段涉及内皮的慢性活化。内皮激活的产生是由于一系列炎症信号（例如细胞因子（如TNF-α）和活性氧（如过氧化氢））的刺激所致，部分是由循环免疫细胞产生的。内皮细胞本身一旦被激活，就会启动细胞质信号转导途径，例如经典的MAPK和SAPK途径，从而导致这些炎症信号中某些基因的表达上调，例如TNF-α和IL-6。糖胺聚糖肝素对平滑肌细胞的生长具有抗增殖作用。肝素处理的被细胞因子TNF-α激活的内皮细胞在分子水平上导致SAPKs JNK和p38的活性降低。可以在上游至少一步观察到这种调节作用，特别是MAPKK MEK3，其响应TNF-α激活p38。还监测了肝素的下游作用。肝素能够减弱JNK底物转录因子c-Jun的磷酸化。肝素还导致由TNF-α诱导的应激纤维形成减少，该作用受p38 / MAPKAPK-2 / HSP27途径调节。酪氨酸磷酸酶抑制剂原钒酸钠可逆转肝素对SAPK活化的减弱作用，进一步的实验表明，肝素以浓度和时间依赖性方式增加DSP MKP-1。另外，发现肝素对SAPK途径的作用对cGK抑制剂敏感，表明cGMP / cGK途径在肝素对SAPK途径的调节中的作用。肝素受体抗体也能够通过减少TNF-α诱导的SAPK激活来模仿肝素。这些共同表明，肝素对活化的内皮细胞具有抗炎和抗氧化作用。最后，研究了SAPK和MAPK途径成员的细胞骨架关联。结果表明，SAM和MAPK的磷酸化形式与细胞骨架成分有关，它们的MAPKK除pMEK7外主要存在于细胞核中。还发现MAPKKK MEKK1和支架蛋白HP-1（两种调节JNK活性的蛋白）与应激纤维有关。

著录项

  • 作者

    Kanyi, Daniela M.;

  • 作者单位

    Lehigh University.;

  • 授予单位 Lehigh University.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 200 p.
  • 总页数 200
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
  • 关键词

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