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疾病，通常是由于突变 LDLR基因，其特征是LDL-C水平严重升高和过早动脉粥样硬化的风险增加 心血管疾病（ASCVD）。尽管降低LDL-C是治疗的无可争议的主要目标，但有 越来越多的证据表明HDL功能在FH中受到损害。该项目的一个主要假设是功能失调 HDL有助于FH患者心血管事件的残留炎症风险。反应性dicarbonyls 包括MDA，Iselg和一个是高反应性的物种，它们迅速加入ApoAI和HDL磷脂 损害HDL功能。我们发现ApoAI和HDL在FH中被MDA和Iselg修饰，以及 该HDL功能因胆固醇外排和抗炎而受到巨大损害 和抗氧化功能。此外，我们最近发现两个小分子dicarbonyl 清道夫，2-HOBA和PPM，提高HDL功能，减少LDL氧化并大大减少 LDLR - / - 缺陷小鼠的动脉粥样硬化，一种FH模型，在缺乏血浆脂质的情况下 水平。另外，病变的特征是坏死的急剧降低，这与 巨噬细胞的存活率增加和胞吞作用。病变具有稳定的动脉粥样硬化斑块的特征， 提出假设，即dicarbonyl清除剂促进了病变的重塑，炎症分辨率和 斑块稳定。因此，在特定的目标1中，我们将研究以下假设。 能够重塑LDLR - / - 小鼠中的动脉粥样硬化病变。我们将研究以下假设 改善的HDL功能可促进炎症分辨率，其特征是巨噬细胞增加 胚细胞增多症和Tregs增加，导致双龙偶治清除剂的抗动脉粥样硬化机制。在 此外，我们还将检验以下假设，即双骨清除的动脉保护作用在很大程度上是 由于保留了HDL功能，通过在HDL缺乏LDLR - / - apoAI-/ - Vs.中进行动脉粥样硬化研究。 LDLR - / - 小鼠。在AIM1C中，我们将研究以下假设：巨噬细胞清道夫受体CD36和SR-BI， 在介导反应性双骨对动脉粥样硬化的影响中起关键作用。这些机械研究 Dicarbonyl清除剂对动脉粥样硬化的影响将为临床翻译研究奠定 人类。最近对2-HOBA的I期研究证明了其在人类中的安全性。因此，具体 AIM 2，我们将检验以下假设：2-HOBA将减少HDL的修饰并改善HDL功能 人类患有杂合FH和患有冠状动脉疾病的受试者没有FH。 2-Hoba的影响 将检查HDL小RNA。最后，我们将检验以下假设：α-me-2-Hoba将有所改善 与2-HOBA相比 迈向开发α-me-2-Hoba作为第二代清道夫的第一步 药代动力学概况的目的是改善HDL功能并减少人类的ASCVD。