Neuro-Circulatory Function in Chronic Heart Failure

该计划项目资助（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之间的互动有很长的历史。我们在这方面的文献作出了重大贡献，现在提出新的研究，探讨更深入的交感神经调节CHF的起源。总体而言，我们认为交感神经激活是由交感神经兴奋性反射增加、交感神经抑制性反射减弱以及中枢神经系统和外周信号分子变化的组合介导的。提出了四个项目。在项目I中，重点将是心力衰竭动物RVLM中ATiR上调的机制。GPCR在激动剂（Ang II）增加的情况下上调的这种独特性质表明该受体在CHF中交感神经兴奋的发病机制中起关键作用。我们将确定ATiR的转录调节的改变和ACE，ACE 2，ROS和运动训练的作用。项目II将集中于PVN在交感神经调节中的作用。基于显示PVN中GABA-谷氨酸系统异常的研究，该项目现在提出，部分由醛固酮调节的上行去甲肾上腺素能通路在CHF的交感兴奋中起重要作用。本研究将探讨醛固酮与nNOS之间的相互作用。最后，将研究运动训练对CHF中nNOS和醛固酮的作用。项目III集中于CHF中的致敏颈动脉化学反射。该项目已清楚地表明CHF中的化学感受器和化学反射增敏以及血管紧张素II和NO对血管球细胞中的K* 通道调节的重要作用，以响应缺氧。这个项目现在的重点是改变颈动脉体血流作为化学反射敏感性介质的作用。这些研究将探讨一种新的转录因子KLF 2在介导内皮细胞剪切应力和K* 通道功能介质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。项目四将调查的作用，骨骼肌反射对交感神经兴奋在充血性心力衰竭。具体来说，该项目将确定ROS是否在改变化学敏感的III组传入和机械敏感的IV组传入的敏感性方面发挥重要作用。运动训练在调节CHF动物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.