INTERACTIONS OF LP(A) WITH VASCULAR EXTRACELLULAR MATRIX

LP(A) 与血管细胞外基质的相互作用

• 批准号: 2885178
• 负责人: Angelo M Scanu
• 金额: $ 27.76万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-16 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2885178
• 关键词: apolipoproteins; atherosclerosis; clinical research; decorin; elastases; enzyme activity; extracellular matrix; fibrinogen; genetically modified animals; human subject; laboratory mouse; low density lipoprotein; macrophage; metalloendopeptidases; protein protein interaction; proteoglycan; recombinant proteins; tissue /cell culture; vascular endothelium

DESCRIPTION (adapted from applicant's abstract): Lipoprotein(a), Lp(a), is a low density lipoprotein (LDL) having as a protein moiety apoB100 linked by a single disulfide bridge to apolipoprotein(a), apo(a), a multikringle structure with a close homology to plasminogen. Lp(a) has been associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD). Vascular retention of Lp(a) via interactions with macromolecules of the extracellular matrix (ECM) of the arterial wall has been among the suggested mechanisms. Since in the atherosclerotic vessel Lp(a) is preferentially retained over LDL, a particle which only contains apoB100, this difference in retention is likely related to the presence of apo(a) in Lp(a). Our studies are designed to test the hypothesis. To this effect, we wish to define the molecular phenotype as well as derivatives thereof obtained by the action of elastases and metalloproteinases (MMPs) which cleave Lp(a)/apo(a). Complementary information will be obtained by using natural mutants of Lp(a) and products generated by recombinant techniques. In terms of proteoglycans (PG), we will continue our studies on decorin which we have already shown to bind to Lp(a) by both electrostatic (apoB100-glycosaminoglycan (GAG)) and hydrophobic interactions (apo(a)-decorin core protein) and extend these studies to the protein core of the other two main PG of the arterial intima, biglycan and versican. All of these PGs will be obtained by both recombinant technology and extraction from arterial tissues from cadavers. We will continue our studies on the binding of Lp(a) and derivatives to fibrinogen also with the goal of defining the molecular basis for the superbinding capacity for fibrinogen of Lp(a) species identified in the plasma of subjects at a high risk for atherosclerotic cardiovascular disease. Moreover the potential cardiovascular pathogenicity of the complexes formed from the in vitro interaction between Lp(a)/apo(a) and matrix macromolecules, will be examined for their susceptibility to the action of proteolytic enzymes with an emphasis on MMPs shown to independently cleave Lp(a)/apo(a) and matrix macromolecules. We will also determine the capacity of these complexes to interact with cultured human macrophages and their potential to stimulate these cells to synthesize and secrete MMPs capable of modifying Lp(a)/apo(a), PGs and derivatives thereof. Underlying these studies is the hypothesis, that the MMP-mediated changes in Lp(a)/apo(a) are favored by the inflammatory milieu of the human atheroma.

描述（改编自申请人的摘要）：脂蛋白（a），Lp（a），是一种 低密度脂蛋白（LDL），其具有作为蛋白质部分的apoB 100，所述apoB 100通过连接的 载脂蛋白（a）的单二硫键，载脂蛋白（a），一种多三环结构 与纤溶酶原具有密切的同源性。Lp（a）与一个 动脉粥样硬化性心血管疾病（ASCVD）的风险增加。血管 通过与细胞外大分子的相互作用保留Lp（a） 基质（ECM）的动脉壁已提出的机制。 由于在动脉粥样硬化血管中Lp（a）优先于LDL保留， 仅含有apoB 100的颗粒，这种保留的差异可能是 与Lp（a）中载脂蛋白（a）的存在有关。我们的研究旨在测试 假设。为此，我们希望将分子表型定义为 以及通过弹性蛋白酶的作用获得的其衍生物， 金属蛋白酶（MMPs），其切割Lp（a）/apo（a）。补充信息 将通过使用Lp（a）的天然突变体和由以下产生的产物来获得： 重组技术。在蛋白聚糖（PG）方面，我们将继续我们的 核心蛋白聚糖的研究，我们已经表明，结合Lp（a）的两个 静电（apoB 100-糖胺聚糖（GAG））和疏水相互作用 （载脂蛋白（a）-核心蛋白聚糖核心蛋白），并将这些研究扩展到 动脉内膜的另外两个主要PG，biglycan和versican。所有 这些PG将通过重组技术和从 尸体的动脉组织我们会继续研究 Lp（a）和衍生物与纤维蛋白原的结合也是为了确定 脂蛋白（a）类与纤维蛋白原超结合能力的分子基础 在动脉粥样硬化高风险受试者的血浆中鉴定 心血管疾病此外， Lp（a）/apo（a）与 基质大分子，将检查其对作用的敏感性 的蛋白水解酶，重点是MMPs显示独立切割 脂蛋白（a）/载脂蛋白（a）和基质大分子。我们还将确定 这些复合物与培养的人巨噬细胞相互作用及其潜力 刺激这些细胞合成和分泌能够修饰 Lp（a）/apo（a）、PG及其衍生物。这些研究的基础是 假设，MMP介导的Lp（a）/apo（a）变化受到 人类动脉粥样硬化的炎症环境。