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首页> 外文学位 >Altered hypoxia-inducible factor-1 alpha levels correlate with coronary artery anomalies.
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Altered hypoxia-inducible factor-1 alpha levels correlate with coronary artery anomalies.

机译：缺氧诱导因子-1α水平的改变与冠状动脉异常相关。

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摘要

The outflow tract myocardium and other regions corresponding to the location of the major coronary vessels of the developing chicken heart, display a high level of hypoxia as assessed by the hypoxia indicator EF5. The EF5 positive tissues are also specifically positive for nuclear-localized hypoxia inducible factor-1 alpha (HIF-1alpha), the oxygen-sensitive component of the hypoxia inducible factor-1 (HIF-1) heterodimer. In this study we altered ambient oxygen levels (hypoxia 15%; hyperoxia 75-40%) during developmental stages (ED 4.5-9, HH 25-35) critical to avian coronary vessel development in order to alter tissue hypoxia, HIF-1alpha protein expression and some of its downstream targets. We also altered gene expression in the embryonic outflow tract myocardium by injecting an adenovirus containing a constitutively active form of HIF-1alpha (AdCA5). Under all experimental conditions, HIF-1alpha reached significant levels. Downstream targets of HIF-1alpha, such as VEGF, PDGF-B and VEGF receptor 2 (VEGFR2), were significant after exposure to the experimental conditions as well. We assayed for coronary anomalies and used 3D reconstructions to specifically identify altered morphology with the coronary vasculature. When incubated for 4.5 days under abnormal oxygen levels or injected with the AdCA5, coronary arteries displayed 13 deviations from their normal proximal connections to the aorta. These deviations were similar to known clinical anomalies of coronary arteries. These findings indicate that developing coronary vessels may be subject to a level of regulation that is dependent on differential oxygen levels within cardiac tissues and subsequent HIF-1 regulation of gene expression.
机译：根据缺氧指标EF5的评估，流出道的心肌和其他与发育中的鸡心主要冠状动脉位置相对应的区域显示出高水平的缺氧。 EF5阳性组织还对核定位的缺氧诱导因子-1α（HIF-1alpha）（缺氧诱导因子-1（HIF-1）异二聚体的氧敏感成分）呈特异性阳性。在这项研究中，我们改变了对禽冠状血管发育至关重要的发育阶段（ED 4.5-9，HH 25-35）的环境氧水平（低氧15％；高氧75-40％），以改变组织缺氧，HIF-1alpha蛋白表达及其一些下游目标。我们还通过注射含有HIF-1alpha（AdCA5）组成型活性形式的腺病毒来改变胚胎流出道心肌中的基因表达。在所有实验条件下，HIF-1alpha均达到显着水平。在暴露于实验条件后，HIF-1alpha的下游靶标（例如VEGF，PDGF-B和VEGF受体2（VEGFR2））也很重要。我们分析了冠状动脉异常，并使用3D重建技术来特异性识别冠状血管的形态改变。当在异常氧气水平下孵育4.5天或注射AdCA5时，冠状动脉显示出与正常主动脉近端连接有13个偏离。这些偏差与已知的冠状动脉临床异常相似。这些发现表明，发育中的冠状血管可能受到一定水平的调节，该水平取决于心脏组织内的不同氧水平和随后的基因表达的HIF-1调节。

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  • 作者

    Wikenheiser, Jamie Christopher.;

  • 作者单位

    Case Western Reserve University.;

  • 授予单位 Case Western Reserve University.;
  • 学科 Biology Physiology.;Biophysics General.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 169 p.
  • 总页数 169
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物物理学;
  • 关键词

  • 入库时间 2022-08-17 11:39:06

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