Particulate Matter Exposure: Cardiovascular Mechanisms

颗粒物暴露：心血管机制

基本信息

批准号：
7387475
负责人：
CHAO-YIN CHEN
金额：
$ 5万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7387475
关键词：
Acute Air Aminobutyric Acid Aminobutyric Acids Animal Model Arrhythmia Arts Breathing Caliber Carbon Cardiac Cardiovascular system Cell Nucleus Data Depressed mood Electrocardiogram Environment Epidemiologic Studies Exercise Exposure to Frequencies Glutamates Health Heart Rate Injection of therapeutic agent Investigation Iron Kinetics Left Measures Mediating Membrane Membrane Potentials Morbidity - disease rate Mus Neurons Particulate Matter Phenotype Potassium Potassium Channel Predisposition Property Recovery Regulation Rest Risk Smoke Soot Soot particle Source Sudden Death Synapses Telemetry Testing Transition Elements Uncertainty Ventricular Arrhythmia Yin air filter base cardiovascular risk factor day exposed human population gamma-Aminobutyric Acid indexing nucleus ambiguus particle particulate pollutant postsynaptic response stressor sudden cardiac death

项目摘要

DESCRIPTION (provided by applicant): Epidemiological studies show significant associations between exposure to particulate matter with particles of aerodynamic diameter of <_2.5 ¿m (PM2.5) and cardiovascular-related morbidity including ventricular arrhythmias and sudden cardiac death. While there appears to be little doubt that PM2.5 exposure poses a significant cardiovascular health risk, the underlying causes are poorly understood. The decreased heart rate variability (HRV) associated with PM2.5 exposure is particularly important since decreased HRV has been shown to be an index of cardiac vagal regulation and is associated with increased susceptibility to ventricular arrhythmias and risk for cardiovascular-related sudden death. Even less understood is the mechanism(s) mediating the reduced HRV and hence the cardiovascular-related morbidity. Using the mouse we propose to use state-of-the-art inhalation facilities to deliver environmentally relevant particulate pollutants (iron/soot) from a true combustion source that captures the carbon-based particles and a transition metal ubiquitous in the environment to test the Hypothesis that short-term (3-day) exposure to PM2.5 results in a reduced HRV due to decreases in the intrinsic membrane properties and/or synaptic excitability of anatomically- and functionally-identified CNS cardiac vagal neurons in the nucleus ambiguous (NA) that regulate HRV. We will test the hypothesis in mice exposed to two concentrations of iron/soot particles and filtered air (FA) as a control by the following Specific Aims. 1. To determine whether short-term (3-day) exposure to PM2.5 in the form of iron/soot particles produces the phenotype of a reduced cardiac vagal regulation of heart rate, by quantifying overall 24-h HRV, diurnal changes in HRV, and heart rate recovery following an acute stressor (exercise). 2. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased intrinsic excitability of the NA cardiac vagal neurons by measuring resting membrane potential, membrane conductance and spiking responses to depolarizing current injections. 3. To determine whether the PM2.5 exposure-induced decreased intrinsic excitability of NA cardiac vagal neurons is mediated by increased potassium currents, left shift in activation kinetics, and/or right shift in inactivation kinetics of three major potassium channels present in NA neurons. 4. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased synaptic excitability by enhanced inhibitory ;?-aminobutyric acid (GABA) mechanisms at the NA cardiac vagal neurons, by measuring the frequency and amplitude of tonic GABA-mediated inhibitory postsynaptic currents (GABA IPSCs). 5. To determine whether the PM2.5 exposure-induced decrease in HRV is mediated by decreased synaptic excitability by depressed glutamatergic (GLU) excitatory mechanisms at the NA cardiac vagal neurons, by measuring the frequency and amplitude of tonic excitatory postsynaptic currents (GLU EPSCs) and the amplitude of evoked GLU EPSCs.

描述（由申请人提供）：流行病学研究表明，接触空气动力学直径 <_2.5 ¿ 的颗粒物之间存在显着关联m (PM2.5) 和心血管相关发病率，包括室性心律失常和心源性猝死虽然毫无疑问，PM2.5 暴露会带来重大的心血管健康风险，但其根本原因却知之甚少。与 PM2.5 暴露相关的心率变异性 (HRV) 尤为重要，因为 HRV 降低已被证明是心脏迷走神经调节的一个指标，并且与室性心律失常的易感性增加和以下风险相关：心血管相关猝死的机制尚不清楚，我们建议使用最先进的吸入设施来输送与环境相关的颗粒污染物。铁/烟灰）来自真正的燃烧源，捕获环境中普遍存在的碳基颗粒和过渡金属，以测试短期（3 天）暴露于 PM2.5 会导致减少的假设HRV 是由于在解剖学和功能上确定的中枢神经系统心脏迷走神经元的内在膜特性和/或突触兴奋性降低而导致的，这些神经元调节 HRV。我们将在暴露于两种浓度的铁/铁的小鼠中检验这一假设。烟尘颗粒和过滤空气 (FA) 作为对照，具体目标如下： 1. 确定短期（3 天）暴露于铁/烟尘颗粒形式的 PM2.5 是否会产生烟尘颗粒和过滤空气 (FA)。通过量化总体 24 小时 HRV、HRV 的昼夜变化以及急性应激源（运动）后的心率恢复，确定心脏迷走神经调节心率降低的表型 2. 确定 PM2.5 暴露是否会导致心率下降。 HRV 由 NA 心脏迷走神经元的内在兴奋性降低介导，通过测量静息膜电位、膜电导和对去极化电流注射的尖峰反应 3. 确定 PM2.5 是否存在。暴露引起的 NA 心脏迷走神经元内在兴奋性降低是由 NA 神经元中存在的三种主要钾通道的钾电流增加、激活动力学左移和/或失活动力学右移介导的。 5 暴露引起的 HRV 降低是通过增强 NA 心脏迷走神经元抑制性 γ-氨基丁酸 (GABA) 机制导致突触兴奋性降低介导的，通过测量强直 GABA 介导的抑制性突触后电流 (GABA IPSC) 5. 通过测量 NA 心脏迷走神经元的谷氨酸能 (GLU) 兴奋机制，确定 PM2.5 暴露引起的 HRV 降低是否是由突触兴奋性降低介导的。强直兴奋性突触后电流 (GLU EPSC) 的频率和幅度以及诱发 GLU EPSC 的幅度。