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: 7750833
• 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
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750833
• 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.

患有心力衰竭（HF）的患者和HF的所有动物模型均表现出增加的交感神经传导性。 激活，这增加了HF期间的死亡风险。这些现象背后的核心机制 对异常的了解很少。我们先前已经观察到， 下丘脑室旁核（PVN）可能有助于提高神经体液驱动。的 这种激活的机制和来源仍有待明确界定。最近我们发现了增强型 兴奋机制，可能是由来自更高的前脑区域， MnPO/SFO和/或上行去甲肾上腺素能输入以及改变的醛固酮-RAS机制 涉及ACE 2。这些数据综合在一起表明， 去甲肾上腺素能输入和PVN内激活的醛固酮-RAS系统（与 这些涉及nNOS的机制）可能参与这种交感神经兴奋。该提案测试了 假设MnPO/SFO激活和去甲肾上腺素能上升机制与 醛固酮-RAS的激活和ACE 2的失活有助于HF中交感神经驱动的增加 我们建议确定1）哪些因素，激活MnPO/SFO，上行去甲肾上腺素能通路或 醛固酮-RAS机制主要负责PVN中nNOS的下调， 2）如果ExT，其使nNOS水平正常化， 抑制系统，也正常化或减少增强的中枢激活和醛固酮-RAS 系统这一目标将通过利用多学科的方法来实现，从完整的 从动物到脑细胞核到单个细胞再到单个分子的研究。我们将使用各种 包括神经解剖学、免疫组织化学、电生理学 分子、细胞和腺病毒/慢病毒基因转移技术。结果将提供重要的新 关于交感神经兴奋的中枢机制的信息，特别是下行神经系统的参与。 和上行输入以及醛固酮-RAS系统的PVN在增加的交感神经 在HF状态下激活。了解这些中央机制的作用，迄今尚未研究 介导增加的交感神经驱动将增强我们治疗HF病症的能力， 心血管并发症 相关性（参见说明）： 慢性心力衰竭（HF）的标志是交感神经驱动增加。这种异常增加了 HF期间的死亡率。虽然在阐明外周机制方面取得了一些进展， 虽然这些异常中涉及的机制，迄今为止确定的机制并不能完全解释升高的 HF期间的神经体液驱动。了解中枢机制的作用和 运动训练将增强我们治疗HF病症及其全身并发症的能力。迄今 有越来越多的证据表明，运动训练是有益的，但涉及的中央机制是 仍有待阐明。