Air Pollution and Hypertension: Vascular Mechanisms

空气污染与高血压：血管机制

• 批准号: 7386664
• 负责人: Sanjay Rajagopalan
• 金额: $ 46.58万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7386664
• 关键词: Acetylcholine; Acute; Address; Air; Air Pollution; Ambulatory Blood Pressure Monitoring; Anabolism; Angiotensin II; Animal Model; Animals; Antioxidants; Area; Ascorbic Acid; Biological; Biological Availability; Blood Pressure; Blood Vessels; Carbon; Chemicals; Chemosensitization; Chronic; Communities; Dependence; Diastolic blood pressure; Elevation; Endothelin-1; Enzymes; Exposure to; F2-Isoprostanes; Factor Analysis; Functional disorder; Future; Generations; Hour; Human; Hypertension; Infusion procedures; Investigation; Lead; Left; Left Ventricular Mass; Link; Measurement; Mediating; Mesentery; Metals; Methods; Mitochondria; Monitor; Mus; NAD(P)H oxidase; New York City; Nitric Oxide; Oxidative Stress; Particulate Matter; Pathway interactions; Penicillamine; Phenylephrine; Placebos; Principal Component Analysis; Production; Public Health; Rate; Reactive Oxygen Species; Research Personnel; Rho-associated kinase; Role; Series; Serotonin; Source; Superoxides; Testing; Time; Transcriptional Activation; Tunica Intima; Up-Regulation; Vasoconstrictor Agents; Ventricular; Week; Xanthine Oxidase; air filter; base; cardiovascular risk factor; day; human AKAP13 protein; human study; improved; indexing; insight; intima media; prevent; programs; research study; response; rho; tetrahydrobiopterin; urinary

DESCRIPTION (provided by applicant): We have recently demonstrated that short-term exposure to PM2.5 results in elevation of blood pressure (BP) in humans and in an animal model. This pro-hypertensive response may be a key mechanism linking PM2.5 to an increase in both short and long-term cardiovascular risk and therefore merits further detailed investigation. We hypothesize that PM2.5 mediated hypertension results from ROS mediated reduction in nitric oxide (*NO) bioavailability and up-regulation of endogenous vasoconstrictor mechanisms. We propose to test this hypothesis in predisposed animal models (where ROS is the predominant basis of hypertension) as well as in humans who have been exposed to air pollution through a series of studies involving a broad interdisciplinary group. In the first specific aim, we will perform studies on C57BI/6 mice that have been exposed to PM2 5 or filtered air (FA) for 8 weeks followed by infusion of angiotensin II (A-ll) or placebo. The effect of PM2.5 on BP, ROS pathways, vascular reactivity and a factor analysis of PM2.5 components most responsible for these effects will be evaluated. In the second specific aim, we will investigate the role of vasoconstrictor pathways activated by ROS in response to PM2.5. In the third specific aim we will assess the impact of strategies that antagonize pathways responsible for heightened ROS production. If our hypothesis is correct, abrogation of ROS generation will improve PM2 5 mediated effects on the vasculature and hypertension. These experiments will provide the basis for the human study where we postulate that BP is significantly modulated by immediate (hours) and short-term (days) alterations in ambient PM2.5 exposure in Detroit and New York City and that increases in BP on exposure to PM2 5 occurs through ROS mediated pathway(s). The effect of ambient air pollution on BP and oxidative stress in humans will be tested. If our hypothesis is correct, then treatment with an antioxidant will significantly blunt or eliminate the relationship between BP and PM2.5 mass. By testing this hypothesized mechanism in detailed animal studies in conjunction with the subsequent corroboration in humans, this proposal offers an unprecedented opportunity to elucidate the physiologically relevant mechanisms responsible for the pro-hypertensive actions of PM2.5 exposure. These insights may lead to future testable methods potentially capable of reducing the tremendous public health burden of PM2.5.

描述（由申请人提供）：我们最近证明，短期接触 PM2.5 会导致人类和动物模型血压 (BP) 升高。这种促高血压反应可能是将 PM2.5 与短期和长期心血管风险增加联系起来的关键机制，因此值得进一步详细研究。我们假设 PM2.5 介导的高血压是由 ROS 介导的一氧化氮 (*NO) 生物利用度降低和内源性血管收缩机制上调所致。我们建议通过涉及广泛的跨学科小组的一系列研究，在易感动物模型（其中活性氧是高血压的主要基础）以及暴露于空气污染的人类中检验这一假设。在第一个具体目标中，我们将对 C57BI/6 小鼠进行研究，这些小鼠已暴露于 PM2 5 或过滤空气 (FA) 8 周，然后输注血管紧张素 II (A-ll) 或安慰剂。将评估 PM2.5 对血压、ROS 途径、血管反应性的影响，并对造成这些影响最重要的 PM2.5 成分进行因子分析。在第二个具体目标中，我们将研究 ROS 激活的血管收缩途径在 PM2.5 反应中的作用。在第三个具体目标中，我们将评估对抗导致 ROS 产生增加的途径的策略的影响。如果我们的假设正确，消除 ROS 的产生将改善 PM2 5 介导的对脉管系统和高血压的影响。这些实验将为人类研究提供基础，我们假设血压会受到底特律和纽约市环境 PM2.5 暴露的即时（小时）和短期（天）变化的显着调节，并且血压会随着暴露而增加PM2.5 通过 ROS 介导的途径发生。将测试环境空气污染对人体血压和氧化应激的影响。如果我们的假设正确，那么抗氧化剂治疗将显着减弱或消除血压和 PM2.5 质量之间的关系。通过在详细的动物研究中测试这一假设机制，并结合随后在人体中的证实，该提议提供了前所未有的机会来阐明与 PM2.5 暴露促高血压作用相关的生理相关机制。这些见解可能会导致未来可测试的方法能够减轻 PM2.5 带来的巨大公共卫生负担。