Regulation of sympathetic function by infarction

描述(由申请人提供)： 这项拟议的研究的长期目标是了解分子 去甲肾上腺素(NE)耗竭和去甲肾上腺素摄取丧失的基础 心肌梗死(MI)后梗死周围交感神经支配。 心肌梗死会导致室性心律失常和心力衰竭， 是美国死亡率和发病率的主要原因。变化 在ML后的心脏神经支配中起着至关重要的作用。 心律失常和心力衰竭，但其基础机制 梗塞周围神经中去甲肾上腺素的耗竭和摄取的丧失 未知。几条证据表明了一种全新的假设 可以解释梗塞周围神经的这些变化。第一, 脑梗塞伴有炎性细胞因子的升高， 尤其是白介素6。交感神经元有受体 IL-6和IL-6家族中的其他细胞因子抑制NE合成和再摄取 在交感神经元中，同时诱导产生包括 血管活性肠肽(VIP)IL-6共享共同的受体和信号 与这些相关细胞因子有关的通路。我们的初步数据表明 IL-6抑制交感神经细胞对NE的摄取并诱导VIP。 因此，我们假设脑梗塞后心脏释放IL-6。 导致神经元NE的耗竭和NE摄取的丧失 梗死区周围的心脏神经支配。 为了验证这一假设，我们将确定：1)IL-6是否抑制去甲肾上腺素和去甲肾上腺素 交感神经元中的合成酶，2)IL-6抑制NE摄取和 交感神经细胞内的NE转运体，3)IL-6抑制新肽Y和 在交感神经元中诱导其他神经肽，以及4)抑制 炎性细胞因子或IL-6在梗死期和梗死期的缺失 预防心肌梗死周围去甲肾上腺素耗竭和去甲肾上腺素摄取丧失 神经支配。各种分子、生化和组织学方法 将用于在体外和体内进行这些实验。这些 研究将确定IL-6是否在糖尿病的病理变化中起关键作用 心肌梗死后的心脏神经支配，并将确定在 其中IL-6调节交感神经功能。这项工作检验了一个新的假说 这将为神经元去甲肾上腺素的耗竭提供一种机制上的解释 和脑梗塞后去甲肾上腺素的摄取，将为脑梗塞的治疗提供科学依据。 这些研究还将为新疗法的开发提供新的和 心脏血管活性多肽表达的重要信息 在脑梗塞后。心脏对IL-6和NE摄取的变化类似 失败也表明，这些研究将产生更多的影响 心肌梗死的治疗。

DESCRIPTION(Provided by applicant): The long term goal of the proposed research is to understand the molecular basis for the depletion of norepinephrine (NE) and loss of NE uptake in the peri-infarct sympathetic innervation following myocardial infarction (MI). Myocardial infarction can lead to ventricular arrhythmias and heart failure, and is a leading cause of mortality and morbidity in the United States. Changes in the cardiac innervation following Ml play a crucial role in the development of arrhythmias and heart failure, but the mechanisms that underlie the depletion of NE and loss of NE uptake in the peri-infarct innervation remain unknown. Several lines of evidence suggest a completely novel hypothesis that can account for these changes in the peri-infarct innervation. First, infarction is accompanied by the elevation of inflammatory cytokines, and interleukin-6 (IL-6) in particular. Sympathetic neurons have receptors for IL-6, and other cytokines in the IL-6 family suppress NE synthesis and reuptake in sympathetic neurons while inducing the production of peptides including vasoactive intestinal peptide (VIP). IL-6 shares common receptors and signaling pathways with these related cytokines. and our preliminary data indicate that IL-6 suppresses NE uptake and induces VIP in cultured sympathetic neurons. Therefore, we hypothesize that IL-6 released in the heart after infarction causes the depletion of neuronal NE and loss of NE uptake observed in the peri-infarct cardiac innervation. To test this hypothesis we will determine if: 1) IL-6 suppresses NE and NE synthetic enzymes in sympathetic neurons, 2) IL-6 suppresses NE uptake and the NE transporter in sympathetic neurons, 3) IL-6 suppresses neunopeptide Y and induces other neuropeptides in sympathetic neurons, and 4) suppression of inflammatony cytokines or the absence of IL-6 during and after infarction prevents the depletion of NE and loss of NE uptake in the peri-infarct cardiac innervation. A variety of molecular, biochemical, and histological approaches will be used to carry out these experiments both in vitro and in vivo. These studies will determine if IL-6 is a key player in the pathological changes in the cardiac innervation following infarction, and will identify the sites at which IL-6 regulates sympathetic function. This work tests a novel hypothesis that would provide a mechanistic explanation for the depletion of neuronal NE and NE uptake following infarction, and will provide the scientific basis for the development of new therapies These studies will also provide new and important information about the expression of vasoactive peptides in the heart following infarction. Similar changes in IL-6 and NE uptake occur during heart failure as well, indicating that these studies will have implications beyond the treatment of myocardial infarction.