INTERACTIONS OF LP(A) WITH VASCULAR EXTRACELLULAR MATRIX

描述(摘自申请人的摘要)：脂蛋白(A)，Lp(A)，是一种 低密度脂蛋白(LDL)，以apoB100为蛋白质部分，通过一种 单二硫键连接载脂蛋白(A)，载脂蛋白(A)，多环结构 与纤溶酶原有密切的同源性。Lp(A)已与一个 动脉粥样硬化性心血管疾病(ASCVD)风险增加。血管 脂蛋白(A)与胞外大分子相互作用的滞留 动脉壁基质(ECM)是可能的机制之一。 由于在动脉粥样硬化血管中Lp(A)比低密度脂蛋白优先保留， 一种只含有apoB100的粒子，这种保留率的差异很可能 与Lp(A)中apo(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 以及通过弹性酶的作用获得的其衍生物和 金属蛋白酶(MMPs)裂解Lp(A)/apo(A)。补充信息 将通过使用Lp(A)的天然突变体和由 重组技术。在蛋白多糖(PG)方面，我们将继续我们的 我们已经证明与Lp(A)结合的核心蛋白的研究 静电(apoB100-糖胺聚糖(GAG))和疏水作用 (Apo(A)-核心蛋白核心蛋白)，并将这些研究扩展到 动脉内膜的另外两个主要PG，Biglycan和Verscan。所有的 这些PG将通过重组技术和从 身体的动脉组织。我们将继续研究 Lp(A)和纤维蛋白原的衍生物也是为了定义 Lp(A)与纤维蛋白原超结合能力的分子基础 在动脉粥样硬化高危人群的血浆中发现 心血管疾病。此外，沙门氏菌对心血管的潜在致病性 Lp(A)/apo(A)与Lp(A)体外相互作用形成的络合物 基质大分子，将被检查其对作用的敏感性 蛋白水解酶，重点是显示出独立切割的MMPs Lp(A)/apo(A)和基质大分子。我们还将确定 这些络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的MMPs Lp(A)/apo(A)、PGs及其衍生物。这些研究的基础是 假设，基质金属蛋白酶介导的Lp(A)/apo(A)的变化有利于 人类动脉粥样硬化的炎性环境。

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.