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首页> 外文学位 >Effects of apolipoprotein(a) on vascular endothelial cell function: Insights into possible physiological and/or pathological roles for lipoprotein(a).
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Effects of apolipoprotein(a) on vascular endothelial cell function: Insights into possible physiological and/or pathological roles for lipoprotein(a).

机译：载脂蛋白（a）对血管内皮细胞功能的影响：脂蛋白（a）可能的生理和/或病理作用的见解。

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摘要

Numerous studies have identified that elevated plasma concentrations of lipoprotein(a) [Lp(a)] are an emerging risk factor for a variety of atherothrombotic disorders. Apolipoprotein(a) [apo(a)], the unique glycoprotein component of Lp(a), consists of tandem repeats of a plasminogen kringle (K) IV-like domain, followed by sequences homologous to the plasminogen KV and protease domains. Apo(a)/Lp(a) has been consistently shown to regulate endothelial function and inhibit plasminogen activation. In the present study, we have demonstrated that apo(a), signaling via integrin alphaVbeta3, is the functional unit in Lp(a) to stimulate in vitro endothelial cell (EC) proliferation and migration, and activate focal adhesion kinase (FAK) and mitogen-activated protein kinases (MAPK) in cultured ECs. Both apo(a) and Lp(a) have also been shown to reduce the levels of active and total transforming growth factor (TGF)-beta in cultured EC medium in an integrin alpha Vbeta3-dependent manner. Despite the stimulatory effects of apo(a) on EC proliferation and migration, we have further confirmed an inhibitory effect of apo(a) on EC in vitro angiogenesis using a fibrin gel tube formation assay. We have provided evidence proving apo(a) inhibits angiogenesis through inhibition of plasminogen activation, and this inhibitory effect is dependent on the presence of apo(a) KV domain. Lastly, apo(a) is shown to reduce the protein levels of annexin A2 and S100A10 in ECs, which implies another potential mechanism by which apo(a)/Lp(a) could impair plasminogen activation on cell surface. In summary, we have discovered the first complete outside-in signaling pathway elicited by apo(a)/Lp(a) in ECs and have built up a connection between the ability of apo(a) to inhibit plasminogen activation and its inhibition of angiogenesis.
机译：大量研究发现，血浆脂蛋白（a）[Lp（a）]浓度升高是多种动脉粥样硬化血栓形成疾病的新兴危险因素。载脂蛋白（a）[apo（a）]是Lp（a）的独特糖蛋白成分，由纤溶酶原kringle（K）IV类结构域的串联重复序列组成，随后是与纤溶酶原KV和蛋白酶结构域同源的序列。 Apo（a）/ Lp（a）一直被证明可调节内皮功能并抑制纤溶酶原激活。在本研究中，我们证明了通过整合素alphaVbeta3发出信号的apo（a）是Lp（a）中的功能单元，可以刺激体外内皮细胞（EC）增殖和迁移，并激活粘着斑激酶（FAK）和ECs中的促分裂原活化蛋白激酶（MAPK）。还显示apo（a）和Lp（a）均可以整联蛋白αVbeta3依赖性方式降低培养的EC培养基中活性和总转化生长因子（TGF）-β的水平。尽管apo（a）对EC的增殖和迁移有刺激作用，但我们使用纤维蛋白凝胶管形成试验进一步证实了apo（a）对EC体外血管生成的抑制作用。我们提供了证明apo（a）通过抑制纤溶酶原激活来抑制血管生成的证据，这种抑制作用取决于apo（a）KV域的存在。最后，显示载脂蛋白（a）可以降低ECs中膜联蛋白A2和S100A10的蛋白质水平，这暗示着载脂蛋白（a）/脂蛋白（a）可能会破坏细胞表面纤溶酶原激活的另一种潜在机制。总而言之，我们发现了EC中由apo（a）/ Lp（a）引发的第一个完整的由外而内的信号传导途径，并且在apo（a）抑制纤溶酶原激活的能力与其对血管生成的抑制之间建立了联系。

著录项

  • 作者

    Liu, Lei.;

  • 作者单位

    Queen's University (Canada).;

  • 授予单位 Queen's University (Canada).;
  • 学科 Biology Molecular.;Biology Physiology.;Health Sciences Pathology.;Chemistry Biochemistry.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 159 p.
  • 总页数 159
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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