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: 10327715
• 负责人: MACRAE F LINTON
• 金额: $ 50.69万
• 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/10327715
• 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; 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，最常见的原因是基因突变 LDLR 基因，其特征是 LDL-C 水平严重升高，并增加过早动脉粥样硬化的风险 心血管疾病（ASCVD）。尽管降低 LDL-C 是无可争议的治疗首要目标，但 越来越多的证据表明 FH 中 HDL 功能受损。该项目的一个主要假设是功能失调 HDL 会增加 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 等高活性物质，可快速与 apoAI 和 HDL 磷脂加合 损害 HDL 功能。我们发现FH中ApoAI和HDL被MDA和IsoLG修饰 HDL 的胆固醇流出能力和抗炎功能显着受损 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，并显着降低 Ldlr-/- 缺陷小鼠（FH 模型）中的动脉粥样硬化，血浆脂质没有显着变化 水平。此外，病变的特点是坏死显着减少，这与 增加巨噬细胞的存活率和胞吞作用。病变具有稳定的动脉粥样硬化斑块的特征， 提出这样的假设：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，我们将检验二羰基清除剂是 能够重塑 Ldlr-/- 小鼠中预先存在的动脉粥样硬化病变。我们将检验以下假设： 改善的 HDL 功能可促进炎症消退，其特征是巨噬细胞增加 胞吞作用和调节性T细胞增多，有助于二羰基清除剂的抗动脉粥样硬化机制。在 此外，我们将检验以下假设：二羰基清除的动脉粥样硬化保护作用在很大程度上是 由于通过在 HDL 缺陷的 Ldlr-/-ApoAI-/- 与 HDL 缺陷的 Ldlr-/-ApoAI-/- 对比中进行动脉粥样硬化研究，保留了 HDL 功能。 Ldlr-/- 小鼠。在 Aim1c 中，我们将检验以下假设：巨噬细胞清道夫受体 CD36 和 SR-BI， 在调节反应性二羰基对动脉粥样硬化的影响中发挥关键作用。这些机制研究 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 2-HOBA 的 I 期研究已证明其对人类的安全性。因此，在具体 目标 2，我们将检验 2-HOBA 会减少 HDL 修饰并改善 HDL 功能的假设 患有杂合子 FH 的人和患有冠状动脉疾病但没有 FH 的受试者。 2-HOBA的影响 将检查 HDL 小 RNA。最后，我们将检验 α-Me-2-HOBA 会有所改善的假设 与 2-HOBA 相比，Ldlr-/- 小鼠的药代动力学特性和更好的减少动脉粥样硬化的能力 开发 α-Me-2-HOBA 作为第二代清除剂的第一步，该清除剂具有改进的 药代动力学特征，旨在改善人类 HDL 功能并减少 ASCVD。