Lipoprotein(a) and Atherosclerosis

描述(申请人提供)：Lp(A)由载脂蛋白(A)和低密度脂蛋白组成。低密度脂蛋白的载脂蛋白(A)和载脂蛋白B-100是共价连接的。血浆Lp(A)浓度超过30 mg/dl是致动脉粥样硬化的，而低密度脂蛋白只有在更高的浓度时才是致动脉粥样硬化的。因此，Lp(A)比人们从其低密度脂蛋白含量中预期的更容易导致动脉粥样硬化。然而，Lp(A)促进动脉粥样硬化发展的机制尚不清楚，部分原因是缺乏表达高水平Lp(A)的小鼠模型。我们最近克服了这一障碍，方法是培育出肝脏高水平表达载脂蛋白(A)的小鼠，并将它们与表达生理水平的人载脂蛋白B-100的小鼠杂交。这些小鼠的血浆中含有Lp(A)和极少的非相关低密度脂蛋白。因此，这些小鼠将提供一个很好的模型来剖析Lp(A)促进动脉粥样硬化的机制。我们将检验这一假设，即apoB-100介导的Lp(A)的蛋白多糖结合和apo(A)组分介导的Lp(A)的纤维蛋白结合有助于Lp(A)的动脉粥样硬化。 为了验证这一假设，我们产生了肝脏高水平表达野生型载脂蛋白(A)或突变形式的载脂蛋白(A)的小鼠，即赖氨酸结合缺陷(LBD)。在特定的目标1中，我们将用表达蛋白多糖结合缺陷低密度脂蛋白的小鼠来培育这些小鼠。因此，我们将有野生型Lp(A)、蛋白多糖结合缺陷Lp(A)、LBD Lp(A)和蛋白多糖结合缺陷/LBD Lp(A)。在具体目标2中，我们将描述这些形式的Lp(A)，展示它们的性质，并评估它们对脂质和脂蛋白谱的影响。我们还将跟进我们有趣的观察结果，即Lp(A)含有高水平的氧化磷脂，而在相同水平表达的低密度脂蛋白则没有。在特定的目标3中，我们将评估Lp(A)与蛋白多糖和纤维蛋白的结合在该小鼠模型动脉粥样硬化发展中的作用。此外，我们将确定Lp(A)中被氧化的磷脂是否有助于其致动脉粥样硬化。建议的研究将增加我们对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.