Project 4: Environmentally Persistent Free Radicals Increase Cardiac Vulnerabilit

项目 4：环境中持久存在的自由基会增加心脏脆弱性

• 批准号: 8097843
• 负责人: Kurt J. Varner
• 金额: $ 14.15万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097843
• 关键词: Address; Anterior Descending Coronary Artery; Antioxidants; Asthma; Attenuated; Biochemical; Biological; Biological Assay; Blood; Breathing; Cardiac; Cardiotoxicity; Cardiovascular Diseases; Cardiovascular system; Catheters; Chemistry; Chlorinated Hydrocarbons; Cytochrome P450; Data; Dose; Down-Regulation; Epidemiologic Studies; Equilibrium; Exposure to; Free Radicals; Functional disorder; Genes; Health; Heart; Histology; Homeostasis; Immunohistochemistry; Incineration; Individual; Infarction; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Ischemia; Left; Left Ventricular Function; Link; Lung; Malignant Neoplasms; Measures; Mediating; Metals; Methods; Morbidity - disease rate; Mus; Myocardial; Myocardial Ischemia; NF-kappa B; NFKB Activation Pathway; Oxidants; Oxidation-Reduction; Oxidative Stress; Particulate; Pathogenesis; Pathway interactions; Pentachlorophenol; Play; Poison; Proteins; Proteomics; Rattus; Reaction; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Resveratrol; Risk; Risk Factors; Role; Sampling; Signal Recognition Particle; Site; Soil; Structure of parenchyma of lung; Sulforaphane; Superfund; Surface; System; Testing; Tissues; Toxic effect; Toxicology; Ventricular Function; Western Blotting; Wood material; base; fly ash; heart dimension/size; in vivo; inhibitor/antagonist; innovation; interdisciplinary approach; mortality; novel; particle; pollutant; pressure; prevent; remediation; response; superfund site; transcription factor

Epidemiological studies consistently show a positive relationship between airborne matter (PM) and increased morbidity and mortality from cardiovascular disease. The mechanisms underlying PM-associated cardiovascular toxicity are largely unknown. We have discovered aromatic chlorinated hydrocarbons combine with metal-containing PM to form surface stabilized, environmentally persistent free radicals (EPFRs). We have shown that EPFRs: 1) are capable of redox cycling and continuously forming reactive oxygen species, 2) produce inflammation and oxidative stress (OS) in the lung, 3) increase the expression of proinflammatory genes in the heart, 4) produce cardiac inflammation, 5) decrease left ventricular function in vivo, and 6) increase OS and the magnitude of cardiac ischemia/reperfusion injury (l/R). These data suggest EPFR mediated OS and inflammation underlies the observed functional deficits and increased vulnerability to l/R injury. Cellular homeostasis in response to OS and inflammation is maintained by the balanced activation of tier 2 antioxidant genes via the transcription factor, Nrf2, and the proinflammatory NfKB pathway. We hypothesize that: EPFR-induced oxidative stress and inflammation enhance cardiac injury and dysfunction by "tipping the balance" between the antioxidant Nrf2 and the proinflammatory NFKB pathway to favor NFKB. TO test this hypothesis, we propose 3 specific aims. Aim 1 will determine the dose-response relationship between EPFRs and cardiac function in vivo and will characterize OS and inflammatory responses in the heart and lungs. Aim 2 will explore the ability of EPFRs to increase infarct size and enhance the deficits in left ventricular function after l/R injury in vivo. Aim 3 will explore the effect of EPFRs exposure on the activity of the Nrf2 antioxidant and NFkB inflammatory pathways. Project 4 relies on the interdisciplinary strengths of the LSU-SRP. Lung tissue from our studies will be analyzed for OS and inflammation in Project 2. Project 5 will examine P450 expression and function with respect to OS in our cardiac tissue. We will also draw heavily on the expertise and analysis performed by the Oxidative Stress Core, while all of the samples tested will be generated by the Materials Core.

流行病学研究一直表明，空气传播物质(PM)与心血管疾病发病率和死亡率的增加呈正相关。PM相关的心血管毒性的潜在机制在很大程度上是未知的。我们发现芳香族氯代烃与含有金属的PM结合形成表面稳定的、环境持久的自由基(EPFR)。我们已经证明了EPFR：1)能够进行氧化还原循环并持续地形成反应性 2)产生炎症和氧化应激(OS)，3)增加心脏促炎基因的表达，4)产生心脏炎症，5)降低在体左心功能，6)增加OS和心脏缺血/再灌注损伤的程度(L/R)。这些数据表明，EPFR介导的OS和炎症是观察到的功能缺陷和对L/R损伤的易感性增加的基础。通过转录因子Nrf2和致炎因子NFkB平衡激活第二层抗氧化剂基因，维持细胞对OS和炎症反应的稳态 路径。我们假设：EPFR诱导的氧化应激和炎症通过改变抗氧化剂Nrf2和促炎NFKB途径之间的平衡，有利于NFKB，从而增强了心脏损伤和功能障碍。为了验证这一假设，我们提出了三个具体目标。目的1将在体内确定EPFR与心功能之间的剂量-反应关系，并将 描述心脏和肺中的OS和炎症反应。目的2探讨EPFR对L缺血再灌注损伤后心肌梗死面积的扩大和左心功能的改善作用。目的3探讨EPFR暴露对NRF2抗氧化剂活性和NFkB炎症通路的影响。项目4依赖于LSU-SRP的跨学科优势。我们研究的肺组织将在项目2中分析OS和炎症。项目5将检查P450在心脏组织中相对于OS的表达和功能。我们还将大量利用氧化应激核心执行的专业知识和分析，而所有测试的样本都将由材料核心生成。