Lipoprotein(a) and Atherosclerosis

性状（申请人提供）：Lp（a）由载脂蛋白（a）和低密度脂蛋白组成。LDL的apo（a）和apoB-100是共价连接的。血浆Lp（a）浓度超过30 mg/dl时，是致动脉粥样硬化的，而LDL仅在更高浓度时才是致动脉粥样硬化的。因此，Lp（a）比从其LDL含量预期的更易致动脉粥样硬化。然而，Lp（a）促进动脉粥样硬化发展的机制知之甚少，部分原因是缺乏表达高水平Lp（a）的小鼠模型。我们最近通过产生具有高水平apo（a）肝脏表达的小鼠并将它们与表达生理水平的人apoB-100的小鼠杂交来克服这一障碍。这些小鼠的血浆含有Lp（a）和很少的非相关LDL。因此，这些小鼠将提供一个很好的模型来剖析Lp（a）导致动脉粥样硬化的机制。我们将检验由apoB-100介导的Lp（a）的蛋白聚糖结合和由apo（a）组分介导的Lp（a）的纤维蛋白结合有助于Lp（a）的致动脉粥样硬化性的假设。 为了验证这一假设，我们产生了野生型载脂蛋白（a）或赖氨酸结合缺陷型（LBD）载脂蛋白（a）突变体肝脏高水平表达的小鼠。在特定目标1中，我们将这些小鼠与表达蛋白聚糖结合缺陷型LDL的小鼠进行繁殖。因此，我们将有野生型Lp（a）、蛋白聚糖结合缺陷型Lp（a）、LBD Lp（a）和蛋白聚糖结合缺陷型/LBD Lp（a）的小鼠。在具体目标2中，我们将表征这些形式的Lp（a），证明其特性，并评估其对脂质和脂蛋白谱的影响。我们还将跟踪我们有趣的观察结果，即Lp（a）含有高水平的氧化磷脂，而LDL在相同水平下表达则没有。在具体目标3中，我们将评估Lp（a）结合蛋白聚糖和纤维蛋白对该小鼠模型中动脉粥样硬化发展的贡献。此外，我们将确定Lp（a）中的氧化磷脂是否有助于其致动脉粥样硬化性。这些研究将增加我们对Lp（a）促进动脉粥样硬化形成的机制的理解，并可能导致更合理的干预手段。

DESCRIPTION (provided by applicant): Lp(a) is composed of apo(a) and LDL. The apo(a) and apoB-100 of the LDL are covalently linked. Plasma concentrations of Lp(a), in excess of 30 mg/dl, are atherogenic, whereas LDL is atherogenic only at much higher concentrations. Therefore, Lp(a) is more atherogenic than one would expect from its content of LDL. However, the mechanisms by which Lp(a) contributes to the development of atherosclerosis are poorly understood, in part because of the lack of murine models expressing high levels of Lp(a). We have recently overcome this obstacle by generating mice with high-level hepatic expression of apo(a) and crossing them with mice that express physiological levels of human apoB-100. The plasma of these mice contains Lp(a) and little if any nonassociated LDL. These mice will therefore provide an excellent model to dissect the mechanisms by which Lp(a) contributes to atherosclerosis. We will test the hypothesis that proteoglycan binding of Lp(a) mediated by apoB-100 and fibrin binding of Lp(a) mediated by the apo(a) component contribute to the atherogenicity of Lp(a). To test this hypothesis, we generated mice with high-level hepatic expression of either wild-type apo(a) or a mutant form of apo(a) that is lysine-binding-defective (LBD). In Specific Aim 1, we will breed these mice with mice expressing proteoglycan-binding-defective LDL. We will therefore have mice with wild-type Lp(a), proteoglycan-binding-defective Lp(a), LBD Lp(a), and proteoglycan-binding-defective/LBD Lp(a). In Specific Aim 2, we will characterize these forms of Lp(a), demonstrate their properties, and assess their effects on lipid and lipoprotein profiles. We will also follow up on our intriguing observation that Lp(a) contains high levels of oxidized phospholipid, whereas LDL expressed at the same level do not. In Specific Aim 3, we will evaluate the contribution of proteoglycan and fibrin binding by Lp(a) to the development of atherosclerosis in this mouse model. In addition, we will determine if the oxidized phospholipid in Lp(a) contributes to its atherogenicity. The proposed studies will increase our understanding of the mechanisms by which Lp(a) contributes to atherogenesis and may lead to more rational means of intervention.