Air Pollution and Hypertension: Vascular Mechanisms

空气污染与高血压：血管机制

• 批准号: 7563931
• 负责人: Sanjay Rajagopalan
• 金额: $ 59.45万
• 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/7563931
• 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; 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; New York City; Nitric Oxide; Oxidases; Oxidative Stress; Particulate Matter; Pathway interactions; Penicillamine; Phenylephrine; Placebos; Principal Component Analysis; Production; Public Health; Reactive Oxygen Species; Research Personnel; Rho-associated kinase; Role; Series; Serotonin; Source; Superoxides; Testing; Time; Tunica Intima; Up-Regulation; Vasoconstrictor Agents; Ventricular; Xanthine Oxidase; air filter; base; cardiovascular risk factor; 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，对PM2.5的短期暴露会导致人类和动物模型中的血压升高（BP）。这种优质反应可能是将PM2.5与短期和长期心血管风险增加的关键机制，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）生物利用度和内源性血管收缩机制上调的降低引起的。我们建议在诱发的动物模型（ROS是高血压的主要基础）以及通过一系列涉及广泛跨学科群体的研究中暴露于空气污染的人类中检验这一假设。在第一个特定目的中，我们将对已暴露于PM2 5或过滤空气（FA）的C57BI/6小鼠进行研究8周，然后输注血管紧张素II（A-LL）或安慰剂。将评估PM2.5对BP，ROS途径，血管反应性和对这些效果最负责的PM2.5成分的因子分析的影响。在第二个特定目的中，我们将研究由ROS激活的血管收缩途径在响应PM2.5时的作用。在第三个特定目的中，我们将评估抗衡ROS产生的途径的策略的影响。如果我们的假设是正确的，则废除ROS的生成将改善PM2 5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，在该研究中，我们假设BP受到底特律和纽约市环境PM2.5暴露的直接（小时）和短期（天（天数）改变，并且通过ROS介导的途径（s）发生BP时，BP在BP暴露时会增加。将测试环境空气污染对BP和人类氧化应激的影响。如果我们的假设是正确的，那么用抗氧化剂的治疗将显着钝或消除BP和PM2.5质量之间的关系。通过测试这种假设的机制在详细的动物研究中与随后在人类中的佐证结合使用，该提案提供了前所未有的机会，以阐明负责PM2.5暴露于PM2.5暴露于生理相关的机制。这些见解可能会导致未来的可测试方法可能能够减轻PM2.5的巨大公共卫生负担。