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

描述(由申请人提供)：心力衰竭患者和所有心力衰竭动物模型都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。标准的治疗方法是试图在心输出量减少的情况下抑制这种交感兴奋。我们以前观察到，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于清楚地描述。最近，我们发现了由1)室旁核内缺氧诱导因子(HIF-1�)机制介导的增强兴奋机制：我们发现，在心力衰竭大鼠的下丘脑室旁核中，HIF-1�蛋白表达增加；向室旁核内注射HIF-1siRNA可使心力衰竭大鼠肾交感神经活动的增加恢复正常。2)肾神经依赖机制：肾去神经术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。我们的初步数据显示，RDN减少了心力衰竭大鼠去甲肾上腺素的排泄，但在假手术大鼠中没有，这表明RDN减少了心力衰竭的交感兴奋。最后，作为一种治疗方式，我们已经表明运动训练(EXT)减少了下丘脑室旁核中HIF-1�的激活，并减少了HF时的神经体液激活。这一建议验证了一种假设，即HIF-1�的激活和/或来自肾神经的上行信息有助于心衰交感神经驱动的增加。此外，EXT可使HF时HIF-1�和/或肾传入传入下丘脑室旁核的水平正常化。我们建议在室旁核水平确定肾神经HIF-1�和/或上行信息的激活以及随后交感神经兴奋的潜在机制。这一目标将通过利用多学科方法来实现，范围从对完整动物的研究到对脑核的研究再到单个神经元。我们将使用多种互补技术，包括电生理、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。这些结果将为交感神经兴奋的中枢机制提供重要的新信息，特别是参与HIF-1�和/或从肾神经到下丘脑室旁核的上行信息在HF状态交感神经激活增加中的作用。了解这些迄今尚未研究过的中枢机制在交感神经驱动增加中的作用，将增强我们治疗心力衰竭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.