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首页> 外文学位 >The role of lipoprotein(a)/apolipoprotein(a) in endothelial dysfunction: Mechanistic studies in vascular endothelium.
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The role of lipoprotein(a)/apolipoprotein(a) in endothelial dysfunction: Mechanistic studies in vascular endothelium.

机译：脂蛋白（a）/载脂蛋白（a）在内皮功能障碍中的作用：血管内皮的机制研究。

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摘要

Multiple lines of evidence suggest that elevated plasma lipoprotein(a) (Lp(a)) concentrations are a significant risk factor for the development of a number of vascular diseases including coronary heart disease and stroke. Lp(a) consists of a low-density lipoprotein (LDL)-like moiety and an unique glycoprotein, apolipoprotein(a) (apo(a)), that is covalently attached to the apolipoproteinB-100 (apoB-100) component of LDL by a single disulfide bond. Many studies have suggested a role for Lp(a) in the process of endothelial dysfunction. Indeed, Lp(a) has been shown to increase both the expression of adhesion molecules on endothelial cells (EC), as well as monocyte and leukocyte chemotactic activity in these cells. We have previously demonstrated that Lp(a), through its apo(a) moiety, increases actomyosin-driven EC contraction which, as a consequence, increases EC permeability. In this thesis, we have demonstrated a role for the strong lysine-binding site in the kringle IV type 10 domain of apo(a) in increasing EC permeability, which occurs through a Rho/Rho kinase-dependent pathway. We have further validated these findings using mouse mesenteric arteries in a pressure myograph system. We also have dissected another major signaling pathway initiated by apo(a) that involves in a disruption of adherens junctions in EC. In this pathway, apo(a)/Lp(a) activates the PI3K/Akt/GSK3beta-dependent pathway to facilitate nuclear translocation of beta-catenin. In the nucleus beta-catenin induced the expression of cyclooxygenase-2 (COX-2) and the secretion of prostaglandin E2 (PGE2) from the EC. Finally, we have presented data to suggest a novel inflammatory role for apo(a) in which it induces the activation of nuclear factor-kappaB through promotion of the dissociation of IkappaB from the inactive cytoplasmic complex; this allows the nuclear translocation of NFkappaB with attendant effects on the transcription of pro-inflammatory genes. Taken together, our findings may facilitate the development of new drug targets for mitigating the harmful effects of Lp(a) on vascular EC which corresponds to an early step in the process of atherogenesis.
机译：多条证据表明血浆脂蛋白（a）（Lp（a））浓度升高是许多血管疾病（包括冠心病和中风）发展的重要危险因素。 Lp（a）由低密度脂蛋白（LDL）样部分和独特的糖蛋白载脂蛋白（a）（apo（a））组成，该蛋白共价附于LDL的载脂蛋白B-100（apoB-100）组分通过一个二硫键。许多研究表明Lp（a）在内皮功能障碍过程中的作用。确实，Lp（a）已显示可增加内皮细胞（EC）上粘附分子的表达以及这些细胞中单核细胞和白细胞的趋化活性。先前我们已经证明Lp（a）通过其apo（a）部分增加了肌动球蛋白驱动的EC收缩，从而增加了EC的通透性。在本论文中，我们证明了apo（a）的10号环蛋白10型结构域中强赖氨酸结合位点在增加EC渗透性中的作用，这是通过Rho / Rho激酶依赖性途径发生的。我们在压力肌电图仪系统中使用小鼠肠系膜动脉进一步验证了这些发现。我们还解剖了由apo（a）引发的另一种主要信号传导途径，该途径涉及EC黏附连接的破坏。在此途径中，载脂蛋白（a）/脂蛋白（a）激活PI3K / Akt / GSK3beta依赖性途径，以促进β-catenin的核转运。在细胞核中，β-catenin诱导了EC中环氧合酶2（COX-2）的表达和前列腺素E2（PGE2）的分泌。最后，我们已经提供了数据，以表明apo（a）的新型炎症作用，其中它通过促进IkappaB从无活性细胞质复合物中的解离来诱导核因子kappaB的激活；这允许NFkappaB的核易位，并伴随促炎基因的转录。综上所述，我们的发现可能有助于减轻Lp（a）对血管EC的有害作用的新药物靶标的开发，这对应于动脉粥样硬化形成过程的早期步骤。

著录项

  • 作者

    Cho, Taewoo.;

  • 作者单位

    Queen's University (Canada).;

  • 授予单位 Queen's University (Canada).;
  • 学科 Biology Molecular.;Biophysics Biomechanics.;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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