Neuro-Circulatory Function in Chronic Heart Failure

本计划项目资助(PPG)更新描述了一系列旨在回答有关慢性心力衰竭(CHF)交感神经兴奋机制的高度相关问题的实验。在这个PPG中，PI之间的互动已经有很长的历史了。我们对这一领域的文献做出了很大贡献，现在正在提议进行新的研究，更深入地探讨CHF中交感神经调节的起源。总体而言，我们认为交感神经的激活是由交感兴奋反射增加、交感抑制反射减弱以及中枢神经系统和外周信号分子的变化共同调节的。提出了四个项目。在项目I中，重点将放在心力衰竭动物的RVLM中ATIR上调的机制上。面对增加的激动剂(Ang II)，GPCR的这种独特的性质被上调，这表明该受体在CHF交感神经兴奋的发病机制中起着关键作用。我们将确定ATIR转录调控的变化以及ACE、ACE2、ROS和运动训练的作用。项目二将侧重于室旁核在交感神经调节中的作用。基于对PVN中GABA-谷氨酸系统异常的研究，该项目现在提出，部分受醛固酮调节的上行去甲肾上腺素能通路在CHF的交感神经兴奋中发挥重要作用。在这个项目中，我们将研究醛固酮和nNOS之间的相互作用。最后，探讨运动训练对慢性充血性心力衰竭患者nNOS和醛固酮的影响。项目III集中于慢性心力衰竭患者的敏化颈动脉化学反射。该项目清楚地显示了CHF中化学感受器和化学反射的敏化，以及Ang II和NO对低氧反应中血管紧张素Ⅱ和一氧化氮调节K~*通道的重要作用。该项目现在专注于颈动脉体部血流改变作为化学反射敏感性的媒介的作用。这些研究将探讨一种新的转录因子KLF2在内皮剪切力和K~*通道功能介体之间的转导中的作用。Ang(1-7)的作用也将在本项目中进行研究。项目四将调查骨骼肌反射在慢性心力衰竭交感神经兴奋中的作用。具体地说，该项目将确定ROS是否在改变化学敏感的III类传入和机械敏感的IV类传入的敏感性方面发挥重要作用。运动训练在调节CHF动物体内ROS生成和抗氧化酶中的作用也将在本项目中进行研究。

This Program Project Grant (PPG) renewal describes a series of experiments designed to answer highly relevant questions concerning the mechanisms for sympatho-excitation in chronic heart failure (CHF). There has been a long history of interaction among the Pi's in this PPG. We have contributed substantially to the literature in this area and are now proposing new studies that probe deeper into the origins of sympathetic regulation in CHF. Overall, we believe that sympathetic activation is mediated by a combination of increased sympatho-excitatory reflexes, blunted sympatho-inhibitory reflexes and changes in signaling molecules in the central nervous system and in the periphery. Four projects are proposed. In Project I the focus will be on the mechanism by which the ATiR is upregulated in the RVLM of animals with heart failure. This unique property of a GPCR to be upregulated in the face of increased agonist (Ang II) suggests a pivotal role for this receptor in the pathogenesis of sympatho-excitation in CHF. We will determine alterations in transcriptional regulation of the ATiR and the roles of ACE, ACE2, ROS and exercise training. Project II will focus on the role of the PVN in sympathetic regulation. Building on studies showing abnormalities in the GABA-glutamate systems in the PVN, this project now proposes that an ascending noradrenergic pathway modulated, in part, by aldosterone plays an important role in sympatho-excitation in CHF. The interactions between aldosterone and nNOS will be examined in this project. Finally, the role of exercise training on nNOS and aldosterone in CHF will be investigated. Project III concentrates on the sensitized carotid chemoreflex in CHF. This project has clearly shown chemoreceptor and chemoreflex sensitization in CHF and an important role for K* channel modulation in glomus cells by Ang II and NO in response to hypoxia. This project now focuses on the role of altered carotid body blood flow as a mediator of chemoreflex sensitivity. These studies will investigate the role of a novel transcription factor, KLF2, in mediating transduction between endothelial shear stress and mediators of K* channel function. The role of Ang (1-7) will also be investigated in this project. Project IV will investigate the role of skeletal muscle reflexes on sympatho-excitation in CHF. Specifically, this project will determine if ROS play an important role in altering the sensitivity of both chemically sensitive group III afferents and mechanically sensitive group IV afferents. The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project.