Project 4: Myocardial Inury and Apoptosis with DE Exposure

长期以来，空气污染与心血管疾病风险增加有关，但确切的 空气污染诱发心肌梗死的发病机制仍然存在， 不完全理解。尽管许多研究已经将血管效应作为主要原因进行了研究， 心肌损伤，只有少数研究调查了吸入污染物的直接毒性作用， 心肌细胞其中一些研究表明，心肌细胞凋亡的发生率增加， 实验暴露后的纤维化，提高了一些致炎性和肌病的可能性， 在临床人群中观察到的影响可能是由直接心肌损伤引起的。因此，我们建议 具体目标如下： 目的1：确定暴露于柴油机废气（DE）是否易患肥大、心力衰竭， 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LV功能和心脏肥大。 我们还将评估细胞凋亡和纤维化，并将用肥大刺激物激发暴露的小鼠， 确定暴露后小鼠是否易患肥大和心力衰竭。 目的2：确定CHF 1/Hey 2（心肌肥大和心力衰竭的重要调节因子）是否 影响了对柴油机尾气的病理反应 我们建议检查实验动物心肌CHF 1/Hey 2表达是否改变 暴露于柴油机废气，然后将评估小鼠的功能丧失或功能获得是否可以 改变他们对柴油机废气的实验反应。 目的3：确定暴露动物和患者的血清介导介质是否会诱导心肌梗死。 毒性，并确定潜在的柴油废气诱导的转录机制。 我们将用暴露动物和患者的血清处理来自未暴露动物的培养心肌细胞， 测量细胞肥大和凋亡，以确定是否有可溶性介质在暴露 患者血清易患这些病理过程中的任何一种。转录基础 通过基因组分析进一步检查肥大或凋亡反应的改变。

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.