Role of HIF1-alpha and Renal afferents in Activation of the PVN in Heart Failure

描述（由申请人提供）：心力衰竭（HF）患者和所有HF动物模型均表现出交感神经激活增加，这增加了发病率和死亡率的风险。标准的治疗方法是在心输出量减少的情况下试图抑制这种交感神经兴奋。我们先前已经观察到，下丘脑室旁核（PVN）内的神经元激活可能有助于这种升高的神经体液驱动。这种激活的机制和来源仍有待明确界定。最近，我们发现了由1）室旁核内缺氧诱导因子（HIF-1 β）机制介导的增强兴奋机制：我们发现HF大鼠室旁核中HIF-1 β蛋白增加;给予室旁核HIF-1 β siRNA使HF大鼠肾交感神经活动正常化。2)肾神经依赖性机制：去肾神经支配（RDN）是减少高血压患者交感神经流出的一种新的有效治疗方法。我们的初步数据表明，RDN减少HF大鼠的去甲肾上腺素排泄，但在假手术大鼠中没有，这表明RDN减少HF的交感兴奋。最后，作为一种治疗方式，我们已经表明，运动训练（ExT）减少了PVN中HIF-1 β的激活，并减少了HF中的神经体液激活。这项提议验证了HIF-1 β和/或来自肾神经的上行信息的激活有助于HF中交感神经驱动增加的假设。此外，ExT可以使HF中的HIF-1 β和/或肾传入输入到PVN的水平正常化。我们建议确定HF大鼠PVN水平上HIF-1 β激活和/或肾神经上行信息以及随后的交感兴奋的潜在机制。这一目标将通过利用多学科的方法来实现，从完整的整个动物的研究到脑细胞核的研究到单个神经元的研究。我们将使用各种互补技术，包括电生理学、神经解剖学、免疫组织化学、分子、细胞和慢病毒基因转移技术。这些结果将提供关于交感神经兴奋的中枢机制的重要新信息，特别是HIF-1 β和/或从肾神经到PVN的上行信息在HF状态下增加交感神经激活中的参与。了解这些中枢机制在交感神经驱动增加中的作用，将提高我们治疗HF及其心血管并发症的能力。

DESCRIPTION (provided by applicant): Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of morbidity and mortality. Standard therapy is to attempt to contain this sympatho- excitation in the face of reduced cardiac output. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to this elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanism mediated by 1) an intra-PVN hypoxia-inducible factor (HIF-1�) mechanism: We have found that HIF-1� protein is increased in the PVN of rats with HF; A HIF-1� siRNA administered to the PVN normalizes the increased renal sympathetic nerve activity in rats with HF. 2) A renal nerve dependent mechanism: Renal denervation (RDN) is a new effective therapy for reducing sympathetic outflow in patients with hypertension. Our preliminary data shows that RDN reduces norepinephrine excretion in rats with HF, but not in sham rats, suggesting that RDN reduces sympatho-excitation in HF. Finally, as a therapeutic modality we have shown that exercise training (ExT) reduces activation of HIF-1� in the PVN and decreases neuro- humoral activation in HF. This proposal tests the hypothesis that activation of HIF-1� and/or ascending information from the renal nerves contributes to the increased sympathetic drive in HF. Furthermore, ExT, may normalizes levels of HIF-1� and/or renal afferent input to the PVN in HF. We propose to determine the underlying mechanisms for the activation of HIF-1� and/or ascending information from the renal nerves at the level of the PVN and subsequent sympatho-excitation in rats with HF. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact whole animals to studies in brain nuclei to individual neurons. We will use a variety of complementary techniques involving electrophysiological, neuroanatomical, immunohistochemical, molecular, cellular, and lentiviral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of HIF-1� and/or ascending information from the renal nerves to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date, in the increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.