Regulation of Sympathetic Function by Infarction

描述（由申请人提供）：心肌梗死后交感神经传递的变化是心律失常、心源性猝死和心力衰竭的主要原因，这些是美国死亡率的主要原因。这项研究的长期目标是了解梗死后交感神经传递改变的分子基础。梗死后心脏神经支配中酪氨酸羟化酶（TH）和去甲肾上腺素转运体（NET）的区域变化可能是导致功能性去神经支配和神经元去甲肾上腺素（NE）耗竭伴随细胞外NE增加的矛盾观察结果的原因。在梗死灶上方，TH升高而NET不变，导致细胞外NE病理性积聚。相比之下，两者在梗塞周围的左心室中都受到抑制，并且梗塞缺乏神经纤维，导致传输损失。初步数据表明，细胞因子和交感神经活动引起TH和NET的区域变化，导致心脏神经传递的异质性。心肌梗死后促肾上腺皮质激素-1相关细胞因子在心脏中升高。这些细胞因子抑制非心脏交感神经元中的去甲肾上腺素能功能。梗塞还引起交感神经系统的激活，其刺激TH、NE的合成，并且在较小程度上刺激NET。这导致了这样的假设，即梗死后心脏交感神经的激活刺激TH的表达，并在较小程度上NET，但这是抵消在左心室梗死诱导的细胞因子，抑制TH和NET的内容。转基因动物将用于测试心脏细胞因子（Aim 1）和增加的神经活性（Aim 2）在梗死后神经传递调节中的作用，并评估对心脏的生理影响。交感神经元培养物和细胞系将用于鉴定去极化和NE刺激NET表达的机制（目的3），并鉴定介导去甲肾上腺素能基因的细胞因子抑制的转录因子（目的4）。这些研究将确定细胞因子和神经活动是否引起梗死后心脏神经元的病理变化，并将确定介导细胞因子和交感神经激活调节TH和NET的机制。这项工作测试新的假设，可以解释有害的改变在心脏后神经支配的分子基础，并导致新的治疗方法的发展。

DESCRIPTION (provided by applicant): Changes in sympathetic neurotransmission after myocardial infarction are a leading contributor to cardiac arrhythmia, sudden cardiac death, and heart failure, which are leading causes of mortality in the United States. The long term goal of the proposed research is to understand the molecular basis for altered sympathetic transmission following infarction. Regional changes in tyrosine hydroxylase (TH) and the norepinephrine transporter (NET) in the post-infarct cardiac innervation may be responsible for the contradictory observations that functional denervation and depletion of neuronal norepinephrine (NE) are accompanied by increased extracellular NE. Above the infarct, TH is elevated while NET is unchanged, leading to a pathological buildup of extracellular NE. In contrast, both are suppressed in the peri-infarct left ventricle, and the infarct is devoid of nerve fibers, resulting in the loss of transmission. Preliminary data suggest that cytokines and sympathetic nerve activity cause the regional changes in TH and NET that lead to heterogeneity in neurotransmission in the heart. Cardiotrophin-1 related cytokines are elevated in the heart after infarction. These cytokines suppress noradrenergic function in non-cardiac sympathetic neurons. Infarction also causes activation of the sympathetic nervous system, which stimulates TH, NE synthesis, and to a lesser degree, NET. This leads to the hypothesis that post-infarct activation of cardiac sympathetic nerves stimulates expression of TH, and to a lesser extent NET, but this is countered in the left ventricle by infarction-induced cytokines that suppress TH and NET content. Transgenic animals will be used to test the role of cardiac cytokines (Aim 1) and increased nerve activity (Aim 2) in the regulation of neurotransmission after infarction, and to assess the physiological impact on the heart. Sympathetic neuron cultures and a cell line will be used to identify mechanisms by which depolarization and NE stimulate NET expression (Aim 3), and to identify transcription factors that mediate cytokine suppression of noradrenergic genes (Aim 4). These studies will determine if cytokines and nerve activity cause the pathological changes in post-infarct cardiac neurons, and will identify mechanisms that mediate the regulation of TH and NET by cytokines and sympathetic activation. This work tests novel hypotheses that may explain the molecular basis for harmful alterations in the post-cardiac innervation, and lead to the development of novel therapeutics.