The Role of Excitatory Input into the PVN on Increased Sympathetic Drive in Heart

PVN 兴奋性输入对心脏交感神经驱动增强的作用

• 批准号: 8377967
• 负责人: KAUSHIK P PATEL
• 金额: $ 41.97万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8377967
• 关键词: Accounting; Address; Affect; Aldosterone; Animal Model; Animals; Area; Brain; Brain Stem; Cardiovascular system; Cell Nucleus; Cells; Chronic; Data; Down-Regulation; Exercise; Exhibits; Gene Transfer; Goals; Heart; Heart failure; Hypothalamic structure; Individual; Instruction; Mediating; Molecular; Nerve; Neurons; Pathway interactions; Patients; Peripheral; Prosencephalon; Rattus; Risk; Role; Source; System; Techniques; Technology; Testing; Therapeutic; Training; Up-Regulation; Viral Genes; improved; interdisciplinary approach; mortality; noradrenergic; paraventricular nucleus; relating to nervous system; single molecule

Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of mortality during HF. The central mechanisms that underlie these abnormalities are poorly understood. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanisms that may be mediated by an altered input from higher forebrain areas such as MnPO/SFO and/or ascending noradrenergic input as well as an altered Aldosterone-RAS mechanism involving ACE2. These data, taken together, suggest that altered descending as well as ascending noradrenergic input and an activated Aldosterone-RAS system within the PVN (with interactions between these mechanisms involving nNOS) may be involved in this sympatho-excitation. This proposal tests the hypothesis that activation of MnPO/SFO and ascending noradrenergic mechanisms in combination with the activation of Aldosterone-RAS and inactivation of ACE2 contribute to the increased sympathetic drive in HF We propose to determine 1) which factors, activation of MnPO/SFO, ascending noradrenergic pathways or Alodosterone-RAS mechanisms are primarily responsible for the down-regulation of nNOS in the PVN and subsequent sympatho-excitation in rats with HF and 2) if ExT, which normalizes levels of nNOS and the inhibitory system, also normalizes or reduces the enhanced central activation and the Aldosterone-RAS system. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact animals to studies in brain nuclei to individual cells to single molecules. We will use a variety of complementary techniques involving neuroanatomical, immunohistochemical, electrophysiological, molecular, cellular, and Adeno/Lenti viral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of the descending and ascending input as well as the Aldosterone-RAS system to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date mediating increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications. RELEVANCE (See instructions): A hallmark of chronic heart failure (HF) is increased sympathetic drive. This abnormality increases the risk of mortality during HF. While there has been some progress in elucidating the peripheral mechanisms involved in these abnormalities, the mechanisms thus far identified do not totally account for the elevated neuro-humoral drive during HF. Understanding the role of central mechanisms and the therapeutic value of exercise training will enhance our ability to treat the HF condition and its systemic complications. To date there is growing evidence that exercise training is beneficial however the central mechanisms involved are remain to be elucidated.

心力衰竭（HF）患者和所有HF动物模型均表现出交感神经功能增高