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：
8837639
负责人：
Loren Eugene Wold
金额：
$ 38.13万
依托单位：
OHIO STATE UNIVERSITY
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 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837639
关键词：
Acute Address Affect Air Air Pollutants Air Pollution Alveolar Macrophages Animal Model Animals Belief Biological Assay Biological Models Blood Circulation 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 dysfunction 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 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 screening stressor tissue oxygenation vascular abnormality

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.

描述（由申请人提供）：摘要：流行病学研究清楚地表明，污染严重的城市心肺死亡人数有所增加。我们最近发现，长期暴露于 PM2.5 会导致体内收缩和舒张功能障碍。这与目前认为 PM2.5 引起的心脏功能障碍是由于肺部细胞因子释放所致的观点相矛盾。因此，尚不清楚心脏是否直接受到 PM2.5 的影响，或者其他介质是否从肺部释放，并可能通过活性氧的释放，对整个心脏和孤立的心肌细胞产生影响。显然，环境空气颗粒物（例如空气污染）和肥胖现在是西方社会心血管疾病的主要原因。同样明显的是，这两种对心血管系统的压力可能相互作用，从而增强毒性并使结果恶化。该项目旨在解决心肌功能特定水平上的这些潜在相互作用。该假设将在体内（例如，单独缺乏瘦素的 ob/ob 肥胖小鼠并与 MnSOD 或 p47phox 转基因小鼠及其杂合（瘦）同窝小鼠杂交）和体外（例如，从这些小鼠中分离出心肌细胞）进行测试，以确定PM2.5 暴露和肥胖对心血管风险的协同作用，以及 ROS 在这种功能障碍中的作用。虽然很明显，PM2.5 暴露和肥胖在心功能障碍的发病机制中都发挥着核心作用，但对介导这些调节因子作用的机制的理解仍存在重大空白。超声心动图和压力-容量环将用于评估整体心血管功能。将通过基于视频的边缘检测和荧光显微镜分析离体心室肌细胞的机械功能和钙瞬态特性，作为评估 PM2.5 对心脏功能影响的主要生物测定法。实时 RT-PCR 和市售 ELISA 试剂盒将用于检测导致 ROS 产生的机制，以及翻译后修饰和蛋白质组学方法。本研究的目的是确定临床相关浓度的 PM2.5 对完整心肌和心肌细胞的生理和分子影响，并确定这些颗粒对肥胖患者心血管功能的作用。待测试的目标包括：目标#1：确定 ROS 依赖性机制是否介导 PM2.5 暴露引起的瘦小鼠左室收缩功能障碍以及加剧肥胖小鼠的收缩功能障碍。目标 2：确定瘦和肥胖 ob/ob 小鼠暴露于 PM2.5 后介导 ROS 诱导的心肌细胞功能障碍的分子机制。通过这些实验，我们希望更好地确定 PM2.5 暴露在肥胖相关心功能障碍发病机制中的机制。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In vitro particulate matter exposure causes direct and lung-mediated indirect effects on cardiomyocyte function.

体外颗粒物暴露会对心肌细胞功能产生直接和肺介导的间接影响。

DOI：
10.1152/ajpheart.00162.2015
发表时间：
2015-07-01
期刊：
American journal of physiology. Heart and circulatory physiology
影响因子：
0
作者：
M. Gorr;Dane J. Youtz;Clayton M. Eichenseer;K. E. Smith;T. Nelin;E. Cormet;L. Wold
通讯作者：
L. Wold

Epigenetics and cardiovascular disease.

表观遗传学和心血管疾病。

DOI：
发表时间：
2015-05-15
期刊：
影响因子：
6.1
作者：
Delbridge, Lea M D;Mellor, Kimberley M;Wold, Loren E
通讯作者：
Wold, Loren E

Losartan treatment attenuates tumor-induced myocardial dysfunction.

氯沙坦治疗可减轻肿瘤引起的心肌功能障碍。

DOI：
10.1016/j.yjmcc.2015.05.007
发表时间：
2015-08
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Stevens SC;Velten M;Youtz DJ;Clark Y;Jing R;Reiser PJ;Bicer S;Devine RD;McCarthy DO;Wold LE
通讯作者：
Wold LE

Microbial involvement in Alzheimer disease development and progression.

微生物参与阿尔茨海默病的发生和进展。