Brain MAP Kinases - Substrate for Sympathetic Excitation in Heart Failure

在美国，心力衰竭是住院的最常见原因 65岁以上的老年人，这一统计数字预计将随着人口老龄化而增长。 交感神经系统(SNS)过度活动是心脏的主要表现 衰竭综合征，并且是发病率和死亡率的强烈预测因子。最近的研究表明 大脑中神经化学机制的改变有助于SNS活性的增强 心力衰竭。几种兴奋性物质在大脑中大量出现在心脏中 失败了。这些物质包括血管紧张素II(Ang II)、醛固酮(Aldo)和促炎性 细胞因子(PIC)。这三种物质都能增加大脑中活性氧的产生， 但除此之外，完全不清楚他们是如何激活SNS的。我们最近发现，阻止 细胞内丝裂原活化蛋白激酶(MAPK)的三个主要成分之一 大脑中的信号级联大大降低了心力衰竭大鼠的SNS活性。这些 MAPK对活性氧物种的存在敏感，对Ang II、Aldo和Ang II、Aldo和 PIC，当被激活时，会导致产生更多的兴奋性神经化学物质 这可能有助于SNS的持续激活，这是心力衰竭的典型表现。这个 这个项目的总体目标是确定三个主要的MAPK信号在多大程度上 在关键的心血管调节中，通路对兴奋性神经化学环境有贡献 大脑的中心，下丘脑室旁核(PVN)，驱动SNS活动 在心力衰竭方面。在收缩性心力衰竭大鼠和Ang II治疗的正常大鼠中，Aldo 而PIC诱导MAPK活性，我们将确定：1)三大MAPK的作用效果 信号通路对兴奋性介质在下丘脑室旁核表达的影响 下丘脑室旁核MAPK信号转导对SNS活性的影响；3)下丘脑室旁核神经元的细胞表型， 表达MAPK信号的小胶质细胞、星形胶质细胞和血管周围巨噬细胞，以及它们的 对兴奋性介质和交感神经兴奋产生的影响。一种组合 分子、免疫组织化学和电生理技术将被用于 阐明大脑MAPK信号影响SNS活性的机制。我们希望 这些研究将为收缩性心力衰竭的治疗干预确定新的靶点。

Heart failure is the most common reason for hospitalization in the United States among those older than 65 years, and this statistic is expected to grow as the population ages. Overactivity of the sympathetic nervous system (SNS) is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. Recent studies suggest that altered neurochemical mechanisms in the brain contribute to the augmented SNS activity in heart failure. Several excitatory substances appear in the brain in excess quantities in heart failure. These include angiotensin II (ANG II), aldosterone (ALDO) and the pro-inflammatory cytokines (PIC). All three act to increase the production of reactive oxygen species in the brain, but beyond that it is not at all clear how they activate the SNS. We recently found that blocking one of the three major components of the mitogen-activated protein kinase (MAPK) intracellular signaling cascade in the brain substantially reduced SNS activity in rats with heart failure. These MAPKs are sensitive to the presence of reactive oxygen species, respond to ANG II, ALDO and PIC, and, when activated, lead to the production of more excitatory neurochemical substances that may contribute to persistent activation of the SNS, which is typical of heart failure. The overall goal of this project is to determine to what extent the three major MAPK signaling pathways contribute to the excitatory neurochemical milieu in a key cardiovascular regulatory center of the brain, the paraventricular nucleus of hypothalamus (PVN), that drives SNS activity in heart failure. In rats with systolic heart failure and in normal rats treated with ANG II, ALDO and PIC to induce MAPK activity, we will determine: 1) the effects of the three major MAPK signaling pathways on the expression of excitatory mediators in the PVN; 2) the effects of MAPK signaling in the PVN on SNS activity; 3) the phenotypes of the cells in PVN - neurons, microglia, astrocytes, and perivascular macrophages - that express MAPK signaling, and their influences on the production of excitatory mediators and sympathetic excitation. A combination of molecular, immunohistochemical, and electrophysiological techniques will be used to elucidate the mechanisms by which brain MAPK signaling influences SNS activity. We hope these studies will identify novel targets for therapeutic intervention in systolic heart failure.