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

基本信息

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
项目类别：
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

项目摘要

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.

流行病学研究始终显示出空降物质（PM）与心血管疾病的发病率和死亡率增加之间的正相关关系。与PM相关的心血管毒性的基本机制在很大程度上未知。我们发现芳香族氯化烃与含金属的PM结合，形成表面稳定，环境持续的自由基（EPFR）。我们已经证明EPFR：1）能够氧化还原循环并连续形成反应性氧，2）在肺中产生炎症和氧化应激（OS），3）增加心脏中促炎基因的表达，4）4）产生心脏炎症，5）5）减少体内左心室功能，6）增加OS和心脏缺血/再生损伤的幅度（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增加L/R损伤的脆弱性的基础。通过转录因子NRF2和促炎性NFKB的平衡激活，对OS和炎症的响应进行了细胞稳态。路径。我们假设：EPFR诱导的氧化应激和炎症通过在抗氧化剂NRF2和促炎性NFKB途径之间“削减平衡”来增强心脏损伤和功能障碍，以支持NFKB。为了检验这一假设，我们提出了3个具体目标。 AIM 1将确定EPFR和体内心脏功能之间的剂量反应关系表征心脏和肺部的OS和炎症反应。 AIM 2将探索EPFR增加梗塞大小并增强体内L/R损伤后左心室功能的缺陷的能力。 AIM 3将探讨EPFR暴露对NRF2抗氧化剂和NFKB炎症途径活性的影响。项目4依靠LSU-SRP的跨学科优势。在项目2中，将分析我们研究中的肺组织的OS和炎症。项目5将检查与我们的心脏组织中OS相对于OS的P450表达和功能。我们还将大力利用氧化应激核心执行的专业知识和分析，而所有测试的样品将由材料核心产生。