Lipoprotein(a) and Atherosclerosis

脂蛋白(a)和动脉粥样硬化

• 批准号: 7176935
• 负责人: ROBERT E PITAS
• 金额: $ 55.63万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176935
• 关键词: Apolipoprotein E; Apolipoproteins B; Arteries; Atherosclerosis; Binding; Breeding; Development; Enhancers; Event; Fibrin; Goals; Hepatic; Human; Intervention; Lead; Link; Lipids; Lipoprotein (a); Lipoprotein (a-); Lipoproteins; Liver; Low-Density Lipoproteins; Lysine; Mediating; Messenger RNA; Modeling; Mus; Phospholipids; Physiological; Plasma; Property; Proteoglycan; Protocols documentation; Testing; Transgenic Mice; Transgenic Organisms; Vitamin E; apolipoprotein B-100; apolipoprotein B-48; apolipoprotein Lp(a+); atherogenesis; follow-up; insight; mouse model; mutant; prevent; promoter; response

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.

描述（由申请人提供）：Lp(a)由载脂蛋白(a)和LDL组成。LDL的载脂蛋白(a)和载脂蛋白b -100是共价连接的。血浆中Lp(a)浓度超过30 mg/dl会致动脉粥样硬化，而LDL只有在更高浓度时才会致动脉粥样硬化。因此，Lp(a)的致动脉粥样硬化性比其LDL含量预期的更强。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，通过培养具有高水平载脂蛋白(a)肝脏表达的小鼠，并将其与表达生理水平的人类载脂蛋白-100的小鼠杂交。这些小鼠的血浆中含有Lp(a)和少量（如果有的话）非相关的LDL。因此，这些小鼠将提供一个很好的模型来解剖Lp(a)促进动脉粥样硬化的机制。我们将验证由载脂蛋白b -100介导的Lp(a)的蛋白聚糖结合和由载脂蛋白(a)成分介导的Lp(a)的纤维蛋白结合导致Lp(a)的动脉粥样硬化的假设。