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首页> 外文学位 >The role of allograft inflammatory factor-1 in vascular smooth muscle cell activation and development of vascular proliferative disease.
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The role of allograft inflammatory factor-1 in vascular smooth muscle cell activation and development of vascular proliferative disease.

机译：同种异体炎症因子1在血管平滑肌细胞活化和血管增生性疾病发展中的作用。

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摘要

The underlying cause of all vascular proliferative diseases is injury-induced activation of vascular endothelium and vascular smooth muscle cells (VSMC). Activated VSMC proliferate, than migrate from the arterial media to the intima, contributing to neointima formation. Activated immune cells, vascular cells, and their endogenous regulators mediate this complex process. One integral regulator of VSMC activation is allograft inflammatory factor-1 (AIF-1).;AIF-1 is a cytoplasmic scaffold protein, expressed constitutively in lymphoid cells and induced in VSMC by injury. Stable over expression of AIF-1 increases VSMC proliferation and migration in vitro, causes increased injury-induced neointima formation, and increases Rac1 and p38 MAP Kinase activity. Recent studies show a correlation between VSMC expression of AIF-1 and atherosclerosis development. We hypothesize that VSMC over expression of AIF-1 contributes to atherosclerosis development by increasing activity of inflammatory signaling molecules, and that inhibiting VSMC AIF-1 expression will decrease injury-induced neointima formation.;Rat carotid arteries transfected with AIF-1 si RNA adenovirus after balloon angioplasty developed significantly less neointima compared to controls. AIF-1 si RNA transfected VSMC proliferated significantly less than AIF-1 or GFP transfected VSMC, while AIF-1 si RNA transfection did not attenuate AIF-1-mediated migration. p38 inhibition showed that AIF-1-mediated proliferation is dependent on p38 activation while AIF-1-mediated migration is not.;AIF-1 transgenic mice fed a high fat diet showed significantly more atherosclerotic lesions than WT littermates. Boyden Chamber assays showed OxLDL treatment increases VSMC migration but does not effect AIF-1-mediated migration. Expression of migration and inflammatory responsive genes in AIF-1 and XGal transfected VSMC after OxLDL treatment at various time points were examined. MMP-2 and -9 expression did not change. ICAM-1 and VCAM-1 expression increased in both groups. AIF-1 VSMC showed significantly higher ICAM-1 expression at baseline and early time points and elevated, but not significantly higher VCAM-1 expression at early time points. Western blots showed increased activation of NF-kB in AIF-1 transfected VSMC at baseline and 30 minutes after OxLDL stimulation compared to XGal transfected VSMC.;Expression of the scavenger receptor receptors CD36 and SRA(I) expression increased after lipid treatment in AIF-1 and XGal transfected groups. AIF-1 VSMC showed sustained expression of both receptors after 16 hours of treatment compared to XGal VSMC, which showed decreased expression at that time point. CXCL16/PSOX expression increased with treatment, but differences in expression patterns were not seen between cell groups. FACS analysis showed significantly more OxLDL was taken up by AIF-1 VSMC compared to XGal VSMC.;These data show that AIF-1 expression in VSMC is tightly linked to the vascular response to injury and development of vascular disease. Although AIF-1-mediated migration is not p38 dependent, AIF-1 may contribute to increased VSMC migration in part by upregulating NF-kB downstream effectors through increased NF-kB activity. AIF-1 may also speed the progression of atherosclerosis by increasing scavenger receptor expression and thereby increasing OxLDL uptake and foam cell formation. Although more study is required to fully elucidate the molecular mechanisms leading to AIF-1 mediated VSMC activation, these data have further established AIF-1 as an integral regulator of the VSMC response to injury.
机译：所有血管增生性疾病的根本原因是损伤诱导的血管内皮和血管平滑肌细胞（VSMC）活化。活化的VSMC增殖，而不是从动脉介质迁移到内膜，从而促进了新内膜的形成。活化的免疫细胞，血管细胞及其内源性调节剂介导这一复杂过程。 VSMC激活的一个整体调节剂是同种异体炎症因子1（AIF-1）。AIF-1是一种细胞质支架蛋白，在淋巴样细胞中组成型表达，并在VSMC中被损伤诱导。 AIF-1的稳定过表达会增加VSMC在体外的增殖和迁移，导致损伤诱导的新内膜形成增加，并增加Rac1和p38 MAP激酶活性。最近的研究表明AIF-1的VSMC表达与动脉粥样硬化发展之间的相关性。我们假设VSMC AIF-1的过表达通过增加炎症信号分子的活性而有助于动脉粥样硬化的发展，并且抑制VSMC AIF-1的表达将减少损伤诱导的新内膜的形成。与对照组相比，球囊血管成形术后的新内膜明显减少。 AIF-1 si RNA转染的VSMC增殖明显少于AIF-1或GFP转染的VSMC，而AIF-1 si RNA转染并未减弱AIF-1介导的迁移。 p38抑制显示AIF-1介导的增殖依赖于p38活化，而AIF-1介导的迁移则不依赖。高脂饮食的AIF-1转基因小鼠的动脉粥样硬化病变明显多于WT同窝仔。 Boyden Chamber实验显示OxLDL处理可增加VSMC迁移，但不影响AIF-1介导的迁移。检查了在不同时间点的OxLDL处理后，AIF-1和XGal转染的VSMC中迁移和炎症反应基因的表达。 MMP-2和-9表达没有变化。两组中ICAM-1和VCAM-1表达均增加。在基线和早期时间点，AIF-1 VSMC显示ICAM-1表达明显升高，而在早期时间点，VIF-1表达却没有显着升高。 Western印迹显示，与XGal转染的VSMC相比，AIF-1转染的VSMC在基线和30分钟后，在OxLDL刺激后NF-kB的激活增加。 1和XGal转染的组。与XGal VSMC相比，AIF-1 VSMC在治疗16小时后显示出两种受体的持续表达，而XGal VSMC则在该时间点表达降低。 CXCL16 / PSOX表达随处理而增加，但在细胞组之间未见表达模式差异。 FACS分析显示，与XGal VSMC相比，AIF-1 VSMC吸收的OxLDL明显更多。这些数据表明，VSMC中AIF-1的表达与血管对损伤的反应和血管疾病的发展密切相关。尽管AIF-1介导的迁移不依赖p38，但AIF-1可能通过增加NF-kB活性上调NF-kB下游效应子来部分促进VSMC迁移。 AIF-1还可以通过增加清除剂受体的表达，从而增加OxLDL的摄取和泡沫细胞的形成来加快动脉粥样硬化的发展。尽管需要更多的研究来充分阐明导致AIF-1介导的VSMC活化的分子机制，但这些数据进一步确定了AIF-1作为VSMC对损伤反应的整体调节剂。

著录项

  • 作者

    Sommerville, Laura Jean.;

  • 作者单位

    Temple University.;

  • 授予单位 Temple University.;
  • 学科 Biology Physiology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 95 p.
  • 总页数 95
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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