Effects of particulate air pollution on HDL function and atherosclerosis

描述(申请人提供)：本项目旨在研究空气颗粒物对高密度脂蛋白功能和动脉粥样硬化的影响。空气污染与严重的不良健康影响有关，导致发病率和死亡率增加。累积的流行病学和实验数据表明，暴露在空气污染物中会导致心血管缺血事件增加和动脉粥样硬化加剧。这些关联似乎与空气颗粒物(PM)成分的相关性更强，更小的颗粒物是最具致病性的。我们发现，超细颗粒(0.185M)优先促进动脉粥样硬化，部分原因是它们在氧化还原循环化学物质中的高含量，以及它们在促进全身组织氧化应激和促炎效应方面与已知的致动脉粥样硬化介质协同作用的能力。事实上，我们最近报道了高度富含超细颗粒的柴油废气颗粒与氧化的磷脂协同诱导人微血管内皮细胞中的大量基因，其中许多属于抗氧化剂(例如，血红素加氧酶-1)、促炎、未折叠蛋白反应或与血管炎症过程相关的促凋亡途径。这些全身性效应导致功能失调的高密度脂蛋白的产生，尽管抗氧化基因上调，但高密度脂蛋白失去抗炎能力，甚至成为促炎因子，抗氧化基因是保护PM毒性的重要防线。我们假设暴露在环境PM中会导致高密度脂蛋白功能失调，并通过诱导全身促氧化剂和促炎性作用来增强动脉粥样硬化，而抗氧化反应的降低将显着增加高密度脂蛋白功能障碍的程度和动脉粥样硬化的发展。我们提出了以下三个具体目标来验证我们的假设：1)表征暴露在空气颗粒物中引起的高密度脂蛋白变化的性质。我们将使用柴油尾气作为模型空气污染物来确定毒理学参数，如有效剂量和诱导高密度脂蛋白功能障碍的动力学。血浆高密度脂蛋白将是广泛的功能和结构表征的对象，其中将包括蛋白质组和脂肪组学方法；2)确定抗氧化反应减少在保护空气污染物促炎效应和动脉粥样硬化方面的作用。我们将使用内皮细胞和巨噬细胞中的条件性血红素加氧酶-1 KO小鼠，以组织特异性的方式研究HO-1消融和氧化应激保护受损对PM诱导的高密度脂蛋白功能障碍和动脉粥样硬化程度的影响；3)通过研究实验暴露于高浓度环境颗粒物是否会导致高密度脂蛋白抗炎和抗氧化功能的改变，评估空气颗粒物与人类高密度脂蛋白功能障碍的关系。这一研究项目代表了候选人先前研究的合乎逻辑的延伸，由于加州大学洛杉矶分校给予的高水平的机构支持；将他确立为环境领域的独立调查员将是极其有价值的。

DESCRIPTION (provided by applicant): This project aims to study the effects of air particulate matter on HDL function and atherosclerosis. Air pollution has been associated with significant adverse health effects leading to increased morbidity and mortality. Cumulative epidemiological and experimental data have shown that exposure to air pollutants lead to increased cardiovascular ischemic events and enhanced atherosclerosis. It appears that these associations are much stronger with the air particulate matter (PM) component and that the smaller particles are the most pathogenic. We have found that ultrafine particles (<0.18 5m) preferentially promote atherosclerosis, partly due to their high content in redox cycling chemicals and their ability to synergize with known proatherogenic mediators in the promotion of systemic tissue oxidative stress and proinflammatory effects. Indeed, we have recently reported that diesel exhaust particles, highly enriched in ultrafines, synergize with oxidized phospholipids in the induction of a large number of genes in human microvascular endothelial cells, many of which belong to antioxidant (e.g. heme oxygenase-1), proinflammatory, unfolded protein response or proapoptotic pathways of relevance in vascular inflammatory processes. These systemic effects result in the generation of dysfunctional HDL, which loses its antiinflammatory capacity or even becomes proinflammatory, despite the upregulation of antioxidant genes, an important line of defense to protect against PM toxicity. We hypothesize that exposure to ambient PM result in dysfunctional HDL and enhanced atherosclerosis via the induction of systemic prooxidant and proinflammatory effects and that a decreased antioxidant response will significantly enhance the degree of HDL dysfunction and development of atherosclerosis. We propose the following three specific aims to test our hypothesis: 1) to characterize the nature of HDL changes induced by the exposure to air particulate matter. We will use diesel exhaust as a model air pollutant to determine toxicological parameters such as effective dose and kinetics involved in the induction of HDL dysfunction. Plasma HDL will be the subject of an extensive functional and structural characterization that will include proteomic and lipidomic approaches; 2) to determine the effects of decreased antioxidant response in the protection against air pollutant proinflammatory effects and atherosclerosis. We will use conditional heme oxygenase-1 KO mice in endothelial cells and macrophages to study the effect of HO-1 ablation and impaired protection against oxidative stress in a tissue-specific manner, on the degree of PM- induced HDL dysfunction and atherosclerosis; 3) to evaluate the relationship between air particulate matter and human HDL dysfunction by studying whether experimental exposures to concentrated ambient particles lead to alteration in HDL antiinflammatory and antioxidant functions. This research project represents a logical extension of the candidate's previous research and thanks to the high level of institutional support given by UCLA; it will be extremely valuable to establish him as an independent investigator in the environmental field.