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。该实验室最近的报告表明，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）小鼠模型中显著改善内皮和enos依赖性血管舒张。基于apoA-l模拟物旨在改善HDL功能，我们假设氧化应激和炎症诱导HDL功能障碍，从而损害血管舒张。在本应用中，我们将在疾病状态和小鼠模型中测试这一假设，其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，但许多人认为慢性炎症状态在SCD损害血管舒张的机制中起作用。该应用程序通过确定镰状红细胞如何引发新的“犯罪伙伴”来诱导血管疾病，研究炎症在损害血管功能障碍中起核心作用的概念。该应用程序的目的是确定炎症、HDL功能和促炎脂质的相互作用，以期确定与镰状红细胞合作损害血管舒张的其他下游“伙伴”。我们将研究急性期蛋白、促炎HDL、促炎脂质和黄嘌呤氧化酶在转基因SCD小鼠血管功能中的作用。重度和非重度SCD患者及对照受试者的血浆生物测定将用于识别和排序损害血管舒张和改变血管壁一氧化氮（no -）和超氧阴离子（O2.-）生成平衡的潜在伴侣。机制将在血管水平上进行研究，以确定SCD如何诱导内皮细胞功能障碍。SCD的造血干细胞移植（HSCT）将被用于测试低密度脂蛋白导致SCD血管舒张受损的替代假设。将apoA-l基因敲除小鼠移植到表达apoA-l缺陷HDL的SCD中，将用于验证D-4F不能改善HDL功能以恢复血管舒张的另一种假设。D-4F在改善预后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，针对HDL可能是一种有效的方法，可以保护慢性炎症疾病的血管功能。通过这些研究，可以实现新的治疗方式，以预防多种以氧化应激和炎症增加为特征的疾病的血管功能障碍。

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.