Project 4: Myocardial Inury and Apoptosis with DE Exposure

空气污染长期以来一直与心血管疾病风险的增加有关，然而，确切的 空气污染致心肌梗死的发病机制仍然存在 不完全理解。尽管许多研究都将血管效应作为主要原因 关于心肌损伤，只有少数研究调查了吸入污染物对心脏的直接毒性影响。 心肌细胞。其中一些研究表明，心肌细胞凋亡的发生率增加 实验性暴露后的纤维化，增加了一些致心律失常和肌病的可能性 在临床人群中看到的影响可能源于直接的心肌损伤。因此，我们建议 以下是具体目标： 目标1：确定接触柴油废气(DE)是否容易导致肥厚、心力衰竭、 体内和体外实验小鼠模型的细胞凋亡、纤维化和心肌梗死。 我们将把野生型小鼠暴露在柴油废气中，然后评估左心功能和心肌肥厚。 我们还将评估细胞凋亡和纤维化，并将挑战暴露在肥大刺激下的小鼠 确定暴露后的小鼠是否易患肥大和心力衰竭。 目的2：确定CHF1/Hey2是心肌肥厚和心力衰竭的重要调节因子。 影响对柴油废气的病理反应。 我们建议研究CHF1/Hey2在实验动物心肌中的表达是否发生改变 暴露于柴油废气中，然后将评估小鼠的功能丧失或功能获得是否可以 改变他们对柴油尾气的实验反应。 目的3：确定暴露在动物和患者体内的血清携带的介质是否会引起心肌梗死 毒性，并确定潜在的柴油尾气诱导转录机制。 我们将用来自暴露的动物和患者的血清来处理来自未暴露的动物的培养的心肌细胞和 检测细胞肥大和细胞凋亡，以确定暴露后是否存在可溶性介质。 易发生上述两种病理过程的患者血清。的转录基础 肥大或凋亡反应的改变将进一步通过基因组分析进行检查。

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.