HDL Dysfunction and Vascular Inflammation

描述（由申请人提供）：本申请的总体目标是确定血管炎症损害血管舒张的机制。来自该实验室的最新报告表明，apoA-1模拟物4F在两种不同的血管疾病-高胆固醇血症和镰状细胞病（SCD）的鼠模型中显著改善内皮依赖性和eNOS依赖性血管舒张。基于apoA-I模拟物被设计为改善HDL功能，我们假设氧化应激和炎症诱导HDL功能障碍，这反过来损害血管舒张。在本申请中，我们将在一种疾病状态和一种小鼠模型中检验这一假设，该模型的血管功能障碍与炎症的关系比高脂血症、镰状细胞病（SCD）更密切。虽然SCD主要是一种遗传性疾病，但许多人认为炎症的慢性状态在SCD损害血管舒张的机制中发挥作用。本申请通过确定镰状红细胞如何产生新的“犯罪伙伴”以诱导血管疾病来研究炎症在损害血管功能障碍中起核心作用的概念。本申请的目的是确定炎症、HDL功能和促炎脂质之间的相互作用，以期鉴定与镰状红细胞合作损害血管舒张的其他下游“伙伴”。我们将研究急性时相蛋白，促炎HDL，促炎脂质和黄嘌呤氧化酶对转基因SCD小鼠血管功能的作用。将使用来自重度和非重度SCD患者和对照受试者的血浆的生物测定来鉴定和分级损害血管舒张并改变一氧化氮（-NO）和超氧阴离子（O2.-）平衡的潜在伴侣。在血管壁中生成。将在血管水平研究机制，以确定SCD如何诱导内皮细胞功能障碍。将SCD的造血干细胞移植（HSCT）到基因工程小鼠中，以检验低密度脂蛋白导致SCD血管舒张受损的替代假设。将SCD的HSCT移植到表达apoA-I缺陷型HDL的apoA-I敲除小鼠中将用于检验D-4F不改善HDL功能以恢复血管舒张的备择假设。D-4F在改善结局方面的效用将在生存水平、缺血性损伤机制、器官病理生物学和HDL与其他炎症介质相互作用的蛋白质组学方面进行测试。在D-4F改善其他系统血管舒张的基础上，我们的数据表明，靶向HDL可能是保护慢性炎症状态疾病血管功能的有效手段。通过这些研究，可以实现新的治疗方式，用于预防以氧化应激和炎症增加为特征的各种疾病中的血管功能障碍。

DESCRIPTION (provided by applicant): The overall goal of this application is to determine the mechanisms by which vascular inflammation impairs vasodilation. Recent reports from this laboratory demonstrate that an apoA-l mimetic, 4F, dramatically improves endothelium-and eNOS-dependent vasodilation in two distinct murine models of vascular disease-hypercholesterolemia and sickle cell disease (SCD). On the basis that apoA-l mimetics were designed to improve HDL function, we hypothesize that oxidative stress and inflammation induce HDL dysfunction, which in turn impairs vasodilation. In this application, we will test this hypothesis in a disease state and a murine model whose vascular dysfunction is more closely associated with inflammation than hyperlipidemia, sickle cell disease (SCD). Although SCD is primarily a genetic disease, many consider the chronic state of inflammation to play a role in the mechanisms by which SCD impairs vasodilation. This application investigates the concept that inflammation plays a central role in impairing vascular dysfunction by determining how the sickling red cell raises up new "partner in crime" to induce vascular disease. The objectives of this application are to determine the interactions between inflammation, HDL function and proinflammatory lipids in hopes of identifying other down-stream "partner(s)" who team up with the sickling red cell to impair vasodilation. We will investigate the role of acute phase proteins, proinflammatory HDL, proinflammatory lipids and xanthine oxidase on vascular function in transgenic SCD mice. Bioassays of plasma from severe and non-severe SCD patients and control subjects will be used to identify and rank potential partners that impair vasodilation and shift the balance of nitric oxide (-NO) and superoxide anion (O2.-) generation in the vessel wall. Mechanisms will be investigated at the vascular level to determine how SCD induces endothelial cell dysfunction. Hematopoietic stem cell transplantation (HSCT) of SCD into genetically engineered mice will be used to test alternative hypotheses that low-density lipoprotein contributes to impaired vasodilation in SCD. HSCT of SCD into an apoA-l knockout mouse that expresses apoA-l-deficient HDL will be used to test the alternative hypothesis that D-4F does not improve HDL function to restore vasodilation. The utility of D-4F in improving outcomes will be tested at the level of survival, mechanisms of ischemic injury, organ pathobiology and proteomics of HDL interactions with other inflammatory mediators. On the basis that D-4F improves vasodilation in other systems, our data suggest that targeting HDL may be an effective means of protecting vascular function in diseases characterized by chronic states of inflammation. Through these studies, new treatment modalities may be realized for preventing vascular dysfunction in a variety of diseases characterized by increases in oxidative stress and inflammation.