Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis

项目摘要 高胆固醇血症和血管炎症是最强的致病因素之一， 动脉粥样硬化的发展和早期动脉粥样硬化病变进展到晚期 脆弱的斑块然而，目前尚不清楚血管胆固醇积累是否直接有助于 血管炎症，特别是巨噬细胞极化成炎性表型。在这 本研究将探讨胆固醇介导的炎症反应的两种机制 巨噬细胞，并将确定其在动脉粥样硬化的发展中的定量意义， 小鼠模型以及相关新生物标志物和治疗方法的转化潜力。中 氧化胆固醇酯（OxCE）诱导Toll样受体4（TLR 4）的二聚化， 其又介导巨噬细胞中的炎症和致动脉粥样硬化反应。在一个动脉粥样硬化保护 机制，我们已经确定了分泌的apoA-I结合蛋白（AIBP）作为一个因素， 通过加速胆固醇流出改善HDL功能，导致脂筏依赖性 TLR 4二聚化和减少巨噬细胞中的炎症反应。我们将测试假设， OxCE促进和AIBP抑制炎性巨噬细胞极化，泡沫细胞形成和炎症性巨噬细胞增殖。 动脉粥样硬化我们已经产生了阻断OxCE的单克隆抗体，以及全身性和全身性抑制剂。 巨噬细胞特异性Apoa 1bp-/-小鼠来测试这些假设。在补充实验中，我们将使用 输注重组AIBP和/或表达AIBP的腺相关病毒以实现增加的AIBP 在血浆中的水平，并期望抑制动脉粥样硬化进展。重要的是，协同研究与其他 PPG项目将检查OxCE和AIBP机制与致动脉粥样硬化或动脉粥样硬化保护的相关性 不同单核细胞和T及B细胞群的功能。为了将我们的发现转化为临床，我们将使用 来自冠状动脉升高的多种族动脉粥样硬化研究（梅萨）受试者的血浆 钙或经历过主要不良心血管事件，以评估诊断和预后价值 新的OxCE和AIBP生物标志物。这些结果将与其他生物标志物进行整合， PPG研究者。为了研究抑制胆固醇诱导的炎症的新治疗方法，我们 将检验在低AIBP血浆中升高AIBP和在高OxCE血浆中阻断OxCE的假设 在梅萨人群中发现的抗动脉粥样硬化药物将减少血浆对人类巨噬细胞的致动脉粥样硬化作用。拟议 研究将增强我们对动脉粥样硬化中胆固醇介导的炎症机制的了解 并将为心血管疾病提供新的生物标志物和治疗策略。

Project Summary Hypercholesterolemia and vascular inflammation are among the strongest causative factors in the development of atherosclerosis and in the progression of early atherosclerotic lesions into advanced vulnerable plaques. However, it is yet unclear whether vascular cholesterol accumulation directly contributes to vascular inflammation and, specifically, to polarization of macrophages into inflammatory phenotypes. In this project, we will investigate two mechanisms, which contribute to cholesterol-mediated inflammatory responses by macrophages, and will determine their quantitative significance in the development of atherosclerosis in a mouse model and the translational potential of relevant new biomarkers and therapeutic approaches. In an atherogenic mechanism, oxidized cholesteryl esters (OxCE) induce dimerization of toll-like receptor-4 (TLR4), which in turn mediates inflammatory and atherogenic responses in macrophages. In an atheroprotective mechanism, we have identified the secreted apoA-I binding protein (AIBP) as a factor, which significantly improves HDL function by accelerating cholesterol efflux, resulting in the disruption of lipid raft-dependent TLR4 dimerization and reduced inflammatory responses in macrophages. We will test the hypotheses that OxCE promotes and AIBP inhibits inflammatory macrophage polarization, foam cell formation and atherosclerosis. We have generated a monoclonal antibody blocking OxCE, as well as systemic and macrophage-specific Apoa1bp-/- mice to test these hypotheses. In complementary experiments, we will use infusions of recombinant AIBP and/or an AIBP-expressing adeno-associated virus to achieve increased AIBP levels in plasma and expect to inhibit atherosclerosis progression. Importantly, synergistic studies with other PPG Projects will examine the relevance of OxCE and AIBP mechanisms to atherogenic or atheroprotective functions of different monocyte and T and B cell populations. To translate our findings into clinic, we will use plasma from Multi-Ethnic Study of Atherosclerosis (MESA) subjects, who have elevated coronary artery calcium or have experienced major adverse cardiovascular events, to evaluate diagnostic and prognostic value of new OxCE and AIBP biomarkers. These results will be integrated with other biomarkers identified by the PPG Investigators. To examine novel therapeutic approaches to restrain cholesterol-induced inflammation, we will test the hypothesis that raising AIBP in the low-AIBP plasma and blocking OxCE in the high-OxCE plasma found in MESA populations will reduce plasma's atherogenic effects on human macrophages. The proposed studies will enhance our mechanistic understanding of cholesterol-mediated inflammation in atherosclerosis and will advance new biomarker and therapeutic strategies for cardiovascular disease.