Apo E mimetics reduce cholesterol and improve HDL function

Apo E 模拟物可降低胆固醇并改善 HDL 功能

• 批准号: 7666804
• 负责人: G M ANANTHARAMAIAH
• 金额: $ 41.33万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7666804
• 关键词: Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins B; Atherogenic Diet; Atherosclerosis; Binding; Cardiovascular Diseases; Cell surface; Cells; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol Homeostasis; Chronic; Clear Cell; Disease; E protein; Electrons; Exhibits; Face; Heparan Sulfate Proteoglycan; Hepatic; Hepatocyte; High Density Lipoproteins; In Vitro; Inflammatory; Knockout Mice; Lead; Lesion; Link; Lipid Peroxides; Lipids; Lipoproteins; Low-Density Lipoproteins; Mediating; Modeling; Mus; New Zealand; Oryctolagus cuniculus; Pathway interactions; Peptides; Plasma; Property; Proteins; Reagent; Recycling; Research; Saline; Tertiary Protein Structure; Therapeutic Agents; Very low density lipoprotein; aryldialkylphosphatase; atherogenesis; cardiovascular risk factor; design; feeding; improved; intravenous administration; mimetics; mouse model; novel; novel therapeutics; particle; public health relevance; receptor binding; reverse cholesterol transport; uptake

DESCRIPTION (provided by applicant): An ideal treatment for atherosclerosis would involve rapid clearance of plasma cholesterol and inhibition of inflammatory pathways. Recent advances in apoA-I mimetic peptides indicate the possibility of improving HDL functions. This proposal deals with ways of incorporating properties of lowering plasma apolipoprotein B- containing lipoproteins with properties of improving HDL function. Our hypothesis is that such peptides would not only retain properties that improve HDL functions, but also enhance the clearance of apoB-containing lipoproteins, thus lowering plasma cholesterol levels. Thus, we designed novel peptides that possesses the cationic putative receptor binding domain from apoE that is covalently linked to an active apoA-I mimetic peptide domain. We have also designed a single-domain cationic peptide to which we have incorporated the lipid hydroperoxide-scavenging properties of apoA-I mimetics. Preliminary results show that these properties enhance uptake of atherogenic lipoproteins in HepG2 cells and inhibit atherosclerosis in apoE null mice. They also appear to improve HDL function. We have exciting results to show that Ac-hE-18A-NH2 dramatically decreases plasma cholesterol in different dyslipidemic mouse models and WHHL rabbits. Preliminary results also show that the peptide possesses antiinflammatory properties. This occurs through a lowering of plasma lipid hydroperoxide levels concomitant with a significant increase in plasma paraoxonase activity. In the WHHL model, the LDL-R pathway is compromised, thus the peptide-mediated atherogenic lipoprotein clearance is likely via the cell surface heparan sulfate proteoglycan (HSPG)-mediated pathway, as described earlier by us in murine models. In a second rabbit model of atherosclerosis, New Zealand White (NZW) rabbits fed an atherogenic diet, a single intravenous administration (3mg/kg) of the peptide significantly decreased total plasma cholesterol levels for 15 days. En face analysis of the lesions after 50 days showed approximately 50% lesion coverage in the saline administered rabbits (control), while little to no lesion in the peptide-treated animals. We therefore hypothesize that both cholesterol-dependent and -independent properties of these novel peptides contribute to the beneficial effects of the peptides to inhibit atherogenesis. We propose two specific aims to further investigate the mechanism of action of these two types of peptides: Specific Aim 1: Effect of peptides on A) uptake of apoB-containing lipoproteins in hepatocytes isolated from different dyslipidemic mouse models and rabbit models and in HepG2 cells. B) Changes in apoA-I and apoE-containing particles and their anti- inflammatory properties. Specific Aim 2: Effect of peptides on A) plasma cholesterol levels, B) lesion inhibition in animal models of atherosclerosis, and C) modulation of HDL properties. Research towards the understanding of the antiatherogenic properties of these novel peptides would yield a better understanding of cholesterol homeostasis and could lead to novel therapeutic reagents that would be useful in the treatment of atherosclerosis and its sequelae. PUBLIC HEALTH RELEVANCE: An ideal treatment for atherosclerosis would involve rapid clearance of plasma cholesterol and inhibition of inflammatory pathways. Recent advances in apoA-I mimetic peptides indicate the possibility of improving HDL function. This proposal deals with ways of incorporating properties of lowering plasma apolipoprotein B- containing lipoproteins with properties of improving HDL function. This is hypothesized to preserve both the anti- inflammatory and cholesterol reducing functions in designed peptides in order to obtain a peptide that would be ideal for the treatment of atherosclerosis and related lipid related inflammatory disorders.

描述（由申请人提供）：动脉粥样硬化的理想治疗方法包括快速清除血浆胆固醇和抑制炎症途径。 apoA-I 模拟肽的最新进展表明改善 HDL 功能的可能性。该提案涉及将降低血浆载脂蛋白 B 的脂蛋白特性与改善 HDL 功能特性相结合的方法。我们的假设是，此类肽不仅保留改善 HDL 功能的特性，而且还能增强含 apoB 脂蛋白的清除率，从而降低血浆胆固醇水平。因此，我们设计了具有来自 apoE 的阳离子推定受体结合结构域的新型肽，该结合结构域与活性 apoA-I 模拟肽结构域共价连接。我们还设计了一种单结构域阳离子肽，其中融入了 apoA-I 模拟物的脂质氢过氧化物清除特性。初步结果表明，这些特性可增强 HepG2 细胞对致动脉粥样硬化脂蛋白的摄取，并抑制 apoE 缺失小鼠的动脉粥样硬化。它们似乎还可以改善 HDL 功能。我们的令人兴奋的结果表明，Ac-hE-18A-NH2 可显着降低不同血脂异常小鼠模型和 WHHL 兔子的血浆胆固醇。初步结果还表明该肽具有抗炎特性。这是通过降低血浆脂质氢过氧化物水平并同时显着增加血浆对氧磷酶活性来实现的。在 WHHL 模型中，LDL-R 途径受到损害，因此肽介导的致动脉粥样硬化脂蛋白清除可能是通过细胞表面硫酸乙酰肝素蛋白聚糖 (HSPG) 介导的途径，如我们之前在小鼠模型中所描述的。在第二个动脉粥样硬化兔子模型中，新西兰白兔（NZW）喂食致动脉粥样硬化饮食，单次静脉注射（3mg/kg）该肽可显着降低血浆总胆固醇水平，持续 15 天。 50 天后对病变的正面分析显示，在施用盐水的兔子（对照）中，病变覆盖率约为 50%，而在肽治疗的动物中，病变覆盖率很小甚至没有。因此，我们假设这些新型肽的胆固醇依赖性和非胆固醇依赖性都有助于肽抑制动脉粥样硬化形成的有益作用。我们提出了两个具体目标来进一步研究这两类肽的作用机制： 具体目标 1：肽对 A) 从不同血脂异常小鼠模型和兔模型分离的肝细胞以及 HepG2 细胞中摄取含 apoB 的脂蛋白的影响。 B) 含有 apoA-I 和 apoE 的颗粒及其抗炎特性的变化。具体目标 2：肽对 A) 血浆胆固醇水平、B) 动脉粥样硬化动物模型中的病变抑制以及 C) HDL 特性调节的影响。了解这些新型肽的抗动脉粥样硬化特性的研究将有助于更好地了解胆固醇稳态，并可能产生可用于治疗动脉粥样硬化及其后遗症的新型治疗试剂。公众健康相关性：动脉粥样硬化的理想治疗方法包括快速清除血浆胆固醇和抑制炎症途径。 apoA-I 模拟肽的最新进展表明改善 HDL 功能的可能性。该提案涉及将降低血浆载脂蛋白 B 的脂蛋白特性与改善 HDL 功能特性相结合的方法。据推测，这可以在设计的肽中保留抗炎和降低胆固醇的功能，以获得对于治疗动脉粥样硬化和相关的脂质相关炎症病症来说是理想的肽。