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

• 批准号: 8663698
• 负责人: Loren Eugene Wold
• 金额: $ 37.66万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-20 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663698
• 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; 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

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效应，如下所示 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，我们希望更好地明确 PM2.5 暴露在肥胖相关心功能障碍发病机制中的机制。