Brain Ang. in Obesity-Induced Hypertension: Role of ER, Oxidant, & Leptin Stress

交感神经系统和血管紧张素II(Ang)与肥胖性高血压(HT)有关，但其机制尚不清楚。我们的初步数据支持脑Ang信号在饮食诱导肥胖(DIO)小鼠动脉压(AP)升高中的作用。更多数据显示，在DIO模型中，内质网(ER)应激在关键的脑心血管控制区(SFO-PVN轴)具有显著的应激作用，并表明化学处理内质网应激影响交感神经活动(SNA)和AP。我们的数据还表明，DIO导致SFO-PVN轴的氧化应激，这与内质网应激有关。此外，新的初步数据显示，在DIO小鼠中，这一脑轴上的内质网应激和氧化应激都与瘦素信号耦合。更多的新数据提出了这样一种可能性，即DIO介导的大脑中的氧化和内质网应激调节了大脑Ang对能量消耗(EE)的促进作用。基于这些有希望的、多方面的初步数据，我们将讨论四个相互关联的创新概念：1)肥胖-HT中控制能量平衡和心血管反应的中枢机制之间的分离；2)作为关键潜在机制的脑ER应激；3)氧化还原信号在肥胖-HT中的作用，与ER应激途径有潜在联系；以及4)SFO-PVN轴作为DIO介导的心血管和代谢失调的主要参与者。我们将解决在DIO小鼠中的总体假设，即在SFO-PVN轴上，脑Ang和/或瘦素信号的增加促进ER应激和氧化应激。我们推测，这种ER/氧化剂应激导致DIO小鼠肾脏SNA和AP增加，但反过来作用于SFO-PVN轴，钝化或逆转Ang和/或Leptin介导的对肥胖-HTN模型中热源性SNA和EE的易化效应。为了解决这一创新假设，我们组装了多种复杂的研究工具，包括1)基因工程小鼠模型和病毒载体，允许大脑部位选择性地靶向关键的Ang、氧化剂和ER应激分子；2)最先进的可视化和量化ER应激的分析方法；3)用于评估AP、SNA和EE的复杂的综合生理学。该项目的一个显著优点是在概念和技术上与项目2和3进行了广泛的对接。

The sympathetic nervous system and angiotensin II (ANG) are implicated in obesity-induced hypertension (HT), but the mechanisms are poorly defined. Our preliminary data support a role for brain ANG signaling in increased arterial pressure (AP) in diet-induced obese (DIO) mice. Additional data reveal striking endoplasmic reticulum (ER) stress in key brain cardiovascular control regions (SFO-PVN axis) in DIO and indicate that chemical manipulation of ER stress influences sympathetic nerve activity (SNA) and AP in this model. Our data also demonstrate that DIO causes oxidative stress in the SFO-PVN axis and this is linked to ER stress. Furthermore, new preliminary data show that both ER stress and oxidative stress in this brain axis are coupled to leptin signaling in DIO mice. Additional new data raise the possibility that DIO-mediated oxidative and ER stress in the brain modulate the facilitatory effect of brain ANG on energy expenditure (EE). Based on these promising, multifaceted preliminary data, we will address four innovative and interrelated concepts: 1) dissociation between central mechanisms controlling energy homeostasis and cardiovascular responses in obesity-HT; 2) brain ER stress, a new disease paradigm, as a key underlying mechanism; 3) the role of redox signaling, with potential links to ER stress pathways, in obesity-HT and 4) the SFO-PVN axis as a major player in DIO-mediated cardiovascular and metabolic dysregulation. We will address the overall hypothesis that in DIO mice, increased brain ANG and/or leptin signaling promotes ER stress and oxidant stress in the SFO-PVN axis. We postulate that this ER/oxidant stress contributes to the increased renal SNA and AP in DIO mice, but conversely acts in the SFO-PVN axis to blunt or reverse brain ANG- and/or leptin-mediated facilitatory effects on thermogenic SNA and EE in this model of obesity-HTN. To address this innovative hypothesis, we have assembled multiple sophisticated research tools, including 1) genetically engineered mouse models and viral vectors that allow brain site-selective targeting of key ANG, oxidant and ER stress molecules; 2) state-of-the-art assays for visualizing and quantifying ER stress; 3) sophisticated integrative physiology for evaluating AP, SNA and EE. A notable strength ofthe project is the extensive interfacing, both conceptual and technical, with Projects 2 and 3.