Dicarbonyl Scavengers to Improve HDL Function and Reduce Atherosclerosis in FH

家族性高胆固醇血症(FH)是一种常染色体显性遗传病，最常见的原因是 低密度脂蛋白受体基因，其特征是低密度脂蛋白-C水平严重升高和过早动脉粥样硬化风险增加 心血管疾病(ASCVD)。尽管降低低密度脂蛋白胆固醇是无可争辩的首要治疗目标，但是 越来越多的证据表明FH患者的高密度脂蛋白功能受损。这个项目的一个主要假设是功能失调 高密度脂蛋白与FH患者心血管事件的残余炎症风险有关。反应性二羰基 包括丙二醛、IsoLG和一种高活性物种，它们能快速与ApoAI和HDL磷脂加成 使高密度脂蛋白功能受损。我们发现，在FH和FH中，载脂蛋白AI和高密度脂蛋白被MDA和IsoLG修饰 在胆固醇流出能力和抗炎能力方面，高密度脂蛋白的功能显著受损。 和抗氧化功能。此外，我们最近还发现了两个小分子二羰基 清道夫，2-HOBA和PPM，改善高密度脂蛋白功能，减少低密度脂蛋白氧化，并显著减少 在没有明显血脂变化的FH模型--LDLR/-缺陷小鼠中的动脉粥样硬化 级别。此外，病变的特点是坏死显著减少，这与 提高巨噬细胞存活率和吞噬功能。病变具有稳定的动脉粥样硬化斑块的特征， 提示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，在特定的目标1中，我们将检验这样的假设，即二羰基清除剂是 能够重塑Ldlr-/-小鼠原有的动脉粥样硬化病变。我们将检验这一假设 以巨噬细胞增多为特征的高密度脂蛋白功能改善促进炎症消退 泡腾作用和增加的Tregs，有助于二羰基清除剂的抗动脉粥样硬化机制。在……里面 此外，我们将检验这样一种假设，即二羰基清除的动脉粥样硬化保护作用在很大程度上是 由于通过对高密度脂蛋白缺乏的Ldlr-/-ApoAI-/-VS进行动脉粥样硬化研究而保留了高密度脂蛋白的功能。 LDLR-/-小鼠。在Aim1c中，我们将检验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方面发挥关键作用。这些机械论研究 二羰基清除剂对动脉粥样硬化的影响将为临床翻译研究奠定基础 人类。最近对2-HOBA进行的第一阶段研究已经证明了它在人类身上的安全性。因此，具体来说， 目的2验证2-HOBA能减少高密度脂蛋白的修饰，改善高密度脂蛋白功能的假说。 杂合子FH患者和无FH的冠心病患者。2-HOBA的影响 在高密度脂蛋白上，将检查小RNA。最后，我们将测试α-me-2-hoa将有所改进的假设 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 将α-Me-2-Hoba开发为第二代清道夫的第一步 以改善人类高密度脂蛋白功能和减少ASCVD为目标的药代动力学研究。

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.