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: 8286866
• 负责人: Loren Eugene Wold
• 金额: $ 32.92万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 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/8286866
• 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

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，在污染严重的城市，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期功能障碍。这与目前认为PM2.5引起的心脏功能障碍是由于细胞因子从肺中释放出来的观点相矛盾。因此，目前尚不清楚心脏是否直接受到PM2.5的影响，或者是否有其他介质从肺中释放出来，并可能通过活性氧释放，对整个心脏和单独的心肌细胞产生影响。很明显，环境空气中的颗粒物(例如，空气污染)和肥胖现在是西方社会心血管疾病的主要诱因。同样明显的是，心血管系统的这两种应激源可能会相互作用，从而增加毒性并恶化结果。该项目旨在解决这些潜在的相互作用，在特定水平的心肌功能。这一假说将在体内(例如，单独的瘦素缺乏ob/ob肥胖小鼠以及与MnSOD或p47Phox转基因小鼠及其杂合(瘦)胎杂交)和体外(例如，从这些小鼠分离的心肌细胞)中进行测试，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PM2.5暴露和肥胖显然都在心脏功能障碍的发病机制中发挥着核心作用，但对这些调节因子作用的机制的理解存在重大空白。超声心动图和压力-容量环将用于评估全球心血管功能。通过基于视频的边缘检测和荧光显微镜分析分离的心室肌细胞的机械功能和钙瞬变特性，作为评估PM2.5对心脏功能影响的主要生物检测方法。实时RT-PCR和商用的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效应，并确定这些颗粒在肥胖患者心血管功能中的作用。测试的目的包括：目的1：确定ROS依赖机制是否介导PM2.5暴露诱导的瘦小鼠左室收缩功能障碍和加重肥胖小鼠的收缩功能障碍。目的2：明确PM2.5暴露后ROS诱导肥胖和肥胖小鼠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作用机制。