Project 4: Myocardial Inury and Apoptosis with DE Exposure

项目 4：DE 暴露引起的心肌损伤和细胞凋亡

• 批准号: 8278532
• 负责人: MICHAEL T CHIN
• 金额: $ 32.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278532
• 关键词: Affect; Air Pollution; Animals; Apoptosis; Apoptotic; Atherosclerosis; Blood Vessels; Breathing; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Cells; Clinical; Diesel Exhaust; Exposure to; Fibrosis; Genomics; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; In Vitro; Incidence; Inflammatory; Infusion procedures; Injury; Ischemia; Measures; Mediator of activation protein; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Oxidative Stress; Pathogenesis; Pathologic Processes; Patients; Phenylephrine; Population; Predisposition; Reperfusion Therapy; Sampling; Serum; Stimulus; Thrombosis; Toxic effect; Ventricular; Wild Type Mouse; base; cardiovascular disorder risk; gain of function; in vivo; loss of function; mouse model; overexpression; pollutant; response; trafficking; vasoconstriction

Air pollution has long been associated with an increased risk of cardiovascular disease, however the exact mechanisms that underlie the pathogenesis of air pollution induced myocardial infarction remain incompletely understood. Although numerous studies have examined vascular effects as the primary cause of myocardial injury, only a few studies have investigated for direct toxic effects of inhaled pollutants on myocardial cells. Some of these studies have suggested an increased incidence of myocardial apoptosis and fibrosis after experimental exposure, raising the possibility that some of the arrhythmogenic and myopathic effects seen in clinical populations may ensue from direct myocardial injury. Accordingly, we propose the following specific aims: Aim 1: Determine whether exposure to diesel exhaust (DE) predisposes to hypertrophy, heart failure, apoptosis, fibrosis and myocardial infarction in vivo and in vitro in experimental mouse models. We will expose wild type mice to diesel exhaust and then assess for LV function and cardiac hypertrophy. We will also assess for apoptosis and fibrosis and will challenge exposed mice with hypertrophic stimuli to determine whether the mice are predisposed to hypertrophy and heart failure after exposure. Aim 2: Determine whether CHF1/Hey2, an important regulator of myocardial hypertrophy and heart failure, affects the pathological response to diesel exhaust. We propose to examine whether myocardial CHF1/Hey2 expression is altered in experimental animals exposed to diesel exhaust, and then will evaluate whether loss of function or gain of function in mice can alter their experimental response to diesel exhaust. Aim 3: Determine whether serum-borne mediators in exposed animals and patients induce myocardial toxicity and identify potential diesel exhaust-induced transcriptional mechanisms. We will treat cultured myocytes from unexposed animals with serum from exposed animals and patients and measure cellular hypertrophy and apoptosis, to determine whether there are soluble mediators in exposed patient serum that predispose to either of these pathological processes. The transcriptional basis for alteration in hypertrophic or apoptotic responses would be further examined by genomic analysis.

长期以来，空气污染一直与心血管疾病风险增加有关，但确切的说法是 空气污染诱发心肌梗死的发病机制仍然存在 不完全理解。尽管大量研究已将血管效应视为主要原因 对于心肌损伤的影响，只有少数研究调查了吸入污染物对心肌损伤的直接毒性作用。 心肌细胞。其中一些研究表明心肌细胞凋亡的发生率增加 实验暴露后纤维化，增加了一些致心律失常和肌病的可能性 在临床人群中观察到的效应可能是由直接心肌损伤引起的。据此，我们建议 以下具体目标： 目标 1：确定接触柴油机尾气 (DE) 是否容易导致肥厚、心力衰竭、 实验小鼠模型体内和体外的细胞凋亡、纤维化和心肌梗死。 我们将野生型小鼠暴露于柴油废气中，然后评估左心室功能和心脏肥大。 我们还将评估细胞凋亡和纤维化，并将用肥大刺激来挑战暴露的小鼠 确定小鼠在暴露后是否容易出现肥大和心力衰竭。 目标 2：确定心肌肥厚和心力衰竭的重要调节因子 CHF1/Hey2 是否 影响柴油机尾气的病理反应。 我们建议检查实验动物心肌 CHF1/Hey2 表达是否发生改变 暴露于柴油机尾气中，然后将评估小鼠的功能丧失或功能获得是否会导致 改变他们对柴油机尾气的实验反应。 目标 3：确定暴露动物和患者体内的血清介质是否会诱发心肌病 毒性并确定潜在的柴油机尾气诱导的转录机制。 我们将用来自暴露动物和患者的血清处理来自未暴露动物的培养的肌细胞， 测量细胞肥大和凋亡，以确定暴露的细胞中是否存在可溶性介质 容易发生这些病理过程的患者血清。转录基础 肥大或凋亡反应的改变将通过基因组分析进一步检查。