Effects of particulate air pollution on HDL function and atherosclerosis

项目描述（申请人提供）：本项目旨在研究空气颗粒物对HDL功能和动脉粥样硬化的影响。空气污染与严重的不利健康影响有关，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，暴露于空气污染物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）成分有更强的关系，而较小的颗粒物是最具致病性的。我们发现，超细颗粒（<0.18 m）优先促进动脉粥样硬化，部分原因是其氧化还原循环化学物质含量高，并且能够与已知的促动脉粥样硬化介质协同促进全身组织氧化应激和促炎作用。事实上，我们最近报道了高度富集超细颗粒的柴油尾气颗粒与氧化磷脂协同诱导人类微血管内皮细胞中的大量基因，其中许多基因属于血管炎症过程中相关的抗氧化（如血红素加氧酶-1）、促炎、未折叠蛋白反应或促凋亡途径。这些全身性影响导致HDL功能失调，失去抗炎能力，甚至变成促炎，尽管抗氧化基因上调，这是防止PM毒性的重要防线。我们假设暴露于环境PM会通过诱导全身促氧化和促炎作用导致HDL功能障碍和动脉粥样硬化加剧，而抗氧化反应的降低将显著提高HDL功能障碍的程度和动脉粥样硬化的发展。我们提出以下三个具体目标来验证我们的假设：1)表征暴露于空气颗粒物引起的HDL变化的性质。我们将使用柴油废气作为模型空气污染物来确定毒理学参数，如诱导HDL功能障碍的有效剂量和动力学。血浆HDL将成为广泛的功能和结构表征的主题，包括蛋白质组学和脂质组学方法；2)确定抗氧化反应降低对空气污染物的抗炎作用和动脉粥样硬化的保护作用。我们将使用内皮细胞和巨噬细胞中的条件血红素氧化酶-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HDL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，来评估空气颗粒物与人体高密度脂蛋白功能障碍之间的关系。该研究项目是候选人先前研究的合理延伸，并感谢加州大学洛杉矶分校给予的高水平机构支持；使他成为环境领域的一名独立调查员将是非常有价值的。

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. PUBLIC HEALTH RELEVANCE This project aims to understand the effects that exposure to air particulate matter produces on HDL function and atherosclerosis, an inflammatory process within the blood vessels that is initiated and propagated by the deposition of lipids and lipoproteins and that is the cause for cardiovascular ischemic diseases such as heart attacks and strokes, responsible for the largest number of deaths in the western world. Air pollution contains both gaseous and particulate components (particulate matter) and it appears that the latter ones are mostly responsible of its cardiovascular toxicity by promoting systemic oxidative stress and proinflammatory effects that result in the loss of HDL antiinflammatory properties. This proposal is designed to characterize the functional and structural HDL modifications that air particulate matter induces with the ultimate goal of helping to develop therapeutic strategies in the future that could allow inhibiting the toxic and harmful effects of air pollutants.