Dicarbonyl Scavengers to Improve HDL Function and Reduce Atherosclerosis in FH

二羰基清除剂可改善 FH 中的 HDL 功能并减少动脉粥样硬化

• 批准号: 10089340
• 负责人: MACRAE F LINTON
• 金额: $ 51.73万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10089340
• 关键词: Anti-Inflammatory Agents; Antiatherogenic; Antibodies; Antiinflammatory Effect; Antioxidants; Arterial Fatty Streak; Atherosclerosis; CD36 gene; CETP gene; Cholesterol; Clinical; Coronary Arteriosclerosis; Development; Disease; Drug Kinetics; Event; Failure; Familial Hypercholesterolemia; Fourier Analysis; Generations; Goals; High Density Lipoproteins; Human; Impairment; Inflammation; Inflammatory; Interleukin-1 beta; LDLR gene; Lesion; Lipids; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Mediating; Mediation; Mendelian randomization; Metabolism; Modeling; Modification; Mus; Mutation; Necrosis; Nicotinic Acids; Patients; Phospholipids; Plasma; Play; Post-Translational Protein Processing; Recurrence; Regulatory T-Lymphocyte; Residual state; Resolution; Risk; Role; Safety; Serum; Small RNA; Testing; Therapeutic; Therapeutic Agents; Uncertainty; adduct; atheroprotective; cardiovascular disorder risk; cardiovascular risk factor; epidemiology study; human disease; improved; inhibitor/antagonist; macrophage; macrophage scavenger receptors; phase 1 study; premature; preservation; prevent; reverse cholesterol transport; secondary analysis; small molecule; targeted treatment; translational study

Familial hypercholesterolemia (FH) is an autosomal dominant disorder, most commonly due to mutations in the LDLR gene, characterized by severely elevated levels of LDL-C and increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Although lowering LDL-C is the undisputed primary goal of therapy, there is mounting evidence that HDL function is impaired in FH. A major hypothesis of this project is that dysfunctional HDL contributes to the residual inflammatory risk of cardiovascular events in FH patients. Reactive dicarbonyls including MDA, IsoLG, and ONE are highly reactive species that rapidly adduct to apoAI and HDL phospholipids impairing HDL function. We have discovered that ApoAI and HDL are modified by MDA and IsoLG in FH and that HDL function is dramatically impaired in terms of cholesterol efflux capacity, as well as anti-inflammatory and antioxidant functions. Furthermore, we have recently discovered that two small molecule dicarbonyl scavengers, 2-HOBA and PPM, improve HDL function, reduce LDL oxidation, and dramatically reduce atherosclerosis in Ldlr-/- deficient mice, a model of FH, in the absence of significant changes in plasma lipid levels. In addition, the lesions were characterized by a dramatic reduction in necrosis, which was associated with increased macrophage survival and efferocytosis. The lesions had features of stable atherosclerotic plaques, suggesting the hypothesis that dicarbonyl scavengers promote lesion remodeling, inflammatory resolution and plaque stabilization. Therefore, in Specific Aim 1, we will examine the hypothesis that dicarbonyl scavengers are capable of remodeling pre-existing atherosclerotic lesions in Ldlr-/- mice. We will examine the hypothesis that improved HDL function promotes inflammatory resolution as characterized by increased macrophage efferocytosis and increased Tregs, contributing to the antiatherogenic mechanisms of dicarbonyl scavengers. In addition, we will test the hypothesis that the atheroprotective effects of dicarbonyl scavenging are in large part due to preservation of HDL functions by performing atherosclerosis studies in HDL deficient Ldlr-/-ApoAI-/- vs. Ldlr-/- mice. In Aim1c, we will examine the hypothesis that macrophage scavenger receptors, CD36 and SR-BI, play critical roles in mediating the impact of reactive dicarbonyls on atherosclerosis. These mechanistic studies of the impact of dicarbonyl scavengers on atherosclerosis will set the stage for a clinical translational study in humans. Recent Phase I studies with 2-HOBA have demonstrated its safety in humans. Therefore, in Specific Aim 2, we will test the hypothesis that 2-HOBA will reduce modification of HDL and improve HDL function in humans with heterozygous FH and in subjects with coronary artery disease without FH. The impact of 2-HOBA on HDL small RNAs will be examined. Finally, we will test the hypothesis that α-Me-2-HOBA will have improved pharmacokinetic attributes and better ability to reduce atherosclerosis in Ldlr-/- mice compared to 2-HOBA, as a first step toward developing α-Me-2-HOBA as a second-generation scavenger that has an improved pharmacokinetic profile with the goal of improving HDL function and reducing ASCVD in humans.

家族性高胆固醇血症（FH）是一种常染色体显性遗传疾病，最常见的是由于基因突变， LDLR基因，以LDL-C水平严重升高和过早动脉粥样硬化风险增加为特征 心血管疾病（ASCVD）。虽然降低LDL-C是无可争议的主要治疗目标，但 越来越多的证据表明高密度脂蛋白功能在FH中受损。这个项目的一个主要假设是， 高密度脂蛋白有助于FH患者心血管事件的残余炎症风险。反应性二羰基 包括MDA、IsoLG和ONE是快速加合到apoAI和HDL磷脂的高反应性物质 损害HDL功能。我们已经发现FH中ApoAI和HDL被MDA和IsoLG修饰， 高密度脂蛋白的功能在胆固醇流出能力和抗炎方面都受到了严重的损害， 和抗氧化功能。此外，我们最近发现，两个小分子二羰基 清除剂，2-HOBA和PPM，改善HDL功能，减少LDL氧化， Ldlr-/-缺陷小鼠（FH模型）中的动脉粥样硬化，在血浆脂质无显著变化的情况下 程度.此外，病变的特征是坏死急剧减少，这与 增加巨噬细胞存活和巨噬细胞增多。病变具有稳定的动脉粥样硬化斑块的特征， 这表明二羰基清除剂促进病变重塑、炎症消退和 斑块稳定因此，在具体目标1中，我们将研究二羰基清除剂是 能够重塑Ldlr-/-小鼠中预先存在的动脉粥样硬化病变。我们将检验这样一个假设， 改善HDL功能促进炎症消退，其特征在于巨噬细胞增加 红细胞增多症和TdR增加，有助于二羰基清除剂的抗动脉粥样硬化机制。在 此外，我们还将检验二羰基清除的动脉粥样硬化保护作用在很大程度上是由于 由于通过在HDL缺陷型Ldlr-/-ApoAI-/- vs. LDLR-/-小鼠。在Aim 1c中，我们将检验巨噬细胞清道夫受体，CD 36和SR-BI， 在介导反应性二羰基化合物对动脉粥样硬化的影响中起关键作用。这些机械研究 二羰基清除剂对动脉粥样硬化的影响将为临床转化研究奠定基础， 人类最近的I期研究2-HOBA已证明其在人体中的安全性。因此，在具体 目的2，我们将检验2-HOBA将减少HDL修饰和改善HDL功能的假设， 在患有杂合子FH的人和患有冠状动脉疾病但不患有FH的受试者中。2-HOBA的影响 对HDL小RNA的影响。最后，我们将检验α-Me-2-HOBA将会改善的假设 与2-HOBA相比，Ldlr-/-小鼠的药代动力学属性和更好的减少动脉粥样硬化的能力，作为一种药物， 开发α-Me-2-HOBA作为第二代清除剂的第一步， 本发明的目的是改善人体中HDL功能和降低ASCVD。