权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Synergistic effects of obesity and air pollution on cardiac function

肥胖和空气污染对心脏功能的协同影响

基本信息

批准号：
8086708
负责人：
Loren Eugene Wold
金额：
$ 33.87万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-20 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8086708
关键词：
Acetylcysteine Acute Address Affect Air Air Pollutants Air Pollution Alveolar Macrophages Animal Model Animals Belief Biological Assay Biological Models Blood Circulation Blood Vessels Bypass Calcium Cardiac Cardiac Myocytes Cardiopulmonary Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Categories Cessation of life Cities Controlled Environment Coronary Arteriosclerosis Data Depressed mood Detection Diabetes Mellitus Echocardiography Elderly Electron Spin Resonance Spectroscopy Endothelium Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Event Exposure to Fluorescence Microscopy Functional disorder Goals Heart In Vitro Investigation Left Ventricular Function Leptin Link Lung Measures Mechanics Mediating Mediator of activation protein Mitochondria Molecular Mus Muscle Cells Muscle function Myocardial tissue Myocardium NADPH Oxidase Obese Mice Obesity Ohio Outcome Oxidants Oxidative Stress Oxygen Consumption Particulate Matter Pathogenesis Pathway interactions Patients Phagocytosis Phenotype Physiological Play Pollution Post Translational Modification Analysis Post-Translational Protein Processing Production Property Proteomics Reactive Oxygen Species Regulation Relative (related person)Respiration Reverse Transcriptase Polymerase Chain Reaction Risk Factors Role Ryanodine Receptors Screening procedure Societies Source System Testing Time Toxic effect Transgenic Mice Transgenic Organisms Ultrafine Ventricular Vulnerable Populations Work abstracting acetovanillone ambient particle antioxidant therapy base cardiovascular risk factor clinically relevant combat cytokine design heart function in vivo novel overexpression particle pressure research study reuptake stressor tissue oxygenation

项目摘要

DESCRIPTION (provided by applicant): Abstract: Epidemiologic studies have clearly shown an increase in cardiopulmonary deaths in heavily polluted cities. We have recently shown that long-term exposure to PM2.5 causes systolic and diastolic dysfunction in vivo. This contradicts the current belief that heart dysfunction caused by PM2.5 is due to cytokine release from the lung. It is therefore not known whether the heart is directly affected by PM2.5, or if other mediators are released from the lung, and possibly through reactive oxygen species release, have an effect on the whole heart and isolated cardiomyocyte. It is clear that ambient air particulate matter (e.g., air pollution) and obesity are now major contributors to cardiovascular disease in western societies. It is also evident that these two stressors to the cardiovascular system may interact to enhance toxicities and worsen outcomes. This project is designed to address these potential interactions, at the specific level of cardiac muscle function. This hypothesis will be tested in in vivo (e.g., leptin-deficient ob/ob obese mice alone and crossed with MnSOD or p47phox transgenic mice and their heterozygous (lean) littermates) and in vitro (e.g., isolated cardiomyocytes from these mice) to determine the synergistic effect of PM2.5 exposure and obesity on cardiovascular risk, as well as the role of ROS in this dysfunction. While it is clear that PM2.5 exposure and obesity both play central roles in the pathogenesis of heart dysfunction, there is a major void in the understanding of the mechanisms that mediate the actions of these regulators. Echocardiography and pressure-volume loops will be used to assess global cardiovascular function. Mechanical function and calcium transient properties of isolated ventricular myocytes will be analyzed by video-based edge detection and fluorescence microscopy as the primary bioassays for assessing the impact of PM2.5 on heart function. Real-time RT-PCR and commercially available ELISA kits will be used to detect mechanisms leading to ROS production, along with post-translational modification and proteomic approaches. The goals of this investigation are to define the physiological and molecular effects of clinically-relevant concentrations of PM2.5 on the intact myocardium and the cardiomyocyte, and to determine the role of these particles on CV function in obesity. The Aims to be tested include: Aim #1: Determine whether ROS-dependent mechanisms mediate PM2.5 exposure-induced LV contractile dysfunction in lean mice and exacerbate contractile dysfunction in obese mice. Aim 2: Define the molecular mechanisms that mediate ROS-induced cardiomyocyte dysfunction following PM2.5 exposure in lean and obese ob/ob mice. With these experiments, we hope to better define the mechanisms of PM2.5 exposure in the pathogenesis of heart dysfunction associated with obesity. PUBLIC HEALTH RELEVANCE: This R01 is designed to test the hypothesis that exposure to PM2.5 depresses CV function via oxidant-mediated pathways in lean animals and will exacerbate obesity-related CV complications by further enhancing oxidative stress.

描述（由申请人提供）：