Chronic Intermittent Hypoxia: Common PVN Adaptations Contribute to Neurogenic Hypertension and Ischemic Neuroprotection

慢性间歇性缺氧：常见的 PVN 适应导致神经源性高血压和缺血性神经保护

• 批准号: 9463471
• 负责人: GLENN M TONEY
• 金额: $ 49.5万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-05 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9463471
• 关键词: Adaptor Signaling Protein; Affect; Angiotensin II; Animals; Antihypertensive Agents; Apoptosis; Brain; Buffers; Chemoreceptors; Chronic; Complex; Conscious; Couples; Coupling; DLG4 gene; DNA Damage; DNA Fragmentation; Data; Development; Electrophysiology (science); Exposure to; Functional disorder; Funding; Gene Transfer; Genes; Genetic Transcription; Glutamate Transporter; Glutamates; Goals; Hypercapnia; Hypertension; Hypoxia; In Vitro; Individual; Infarction; Injury; Ischemia; Ischemic Stroke; Lesion; Link; Maps; Mediating; Microinjections; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Nerve; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Peptides; Pharmacology; Plasma; Population; Production; Prosencephalon; Rattus; Recovery; Regulation; Resistance; Risk; Risk Factors; Signaling Protein; Sleep Apnea Syndromes; Slice; Synapses; Synaptic plasticity; Systemic hypertension; Telemetry; Testing; Time; Tissue Survival; Tissues; Viral; base; excitotoxicity; extracellular; gamma-Aminobutyric Acid; hindbrain; human model; imaging study; in vivo; insight; knock-down; live cell imaging; neuroadaptation; neurogenic hypertension; neuron loss; neuroprotection; neurotoxic; paraventricular nucleus; patch clamp; preservation; prevent; recruit; response; small hairpin RNA; stroke risk; transmission process

Project Summary Sleep apnea (SA) affects ~15% of the US population. Most people with SA develop neurogenic hypertension (HTN) associated with elevated sympathetic nerve activity (SNA). During the previous funding cycle, we modeled SA HTN by exposing rats to chronic intermittent hypoxia (CIH). We determined that HTN induced by 7 days of CIH is maintained by pre-sympathetic PVN neuronal discharge driven by exaggerated NMDA receptor (NMDAR) tone. Importantly, we discovered that PVN activation by CIH involves local adaptive responses (i.e., plasticity) wherein expression of neuronal NMDAR subunits (GluN1 & GluN2B) is reduced and expression of the glial L-glutamate (L-Glu) transporter EEAT2 is increased. These responses reflect homeostatic adaptations to exaggerated glutamatergic input, which we postulate arises, at least in part, from the hindbrain NTS (Project 1) and the forebrain MnPO (Project 2). CIH also decreased PVN expression of the adaptor protein PSD95 that forms a ternary complex with the NMDAR GluN2B subunit and neuronal nitric oxide (NO) synthase (nNOS). This complex couples NMDAR Ca2+ influx with production of NO. We hypothesize that these adaptations to CIH have two offsetting actions. (1) Reduced NMDAR and increased EAAT2 expression blunt glutamatergic PVN activation and thereby buffer development of HTN. (2) Reduced PSD95 blunts NMDAR-driven NO production and lessens its tonic facilitation of GABA release. This disinhibits the PVN and thereby supports development of HTN. The net effect of these opposing adaptations is that HTN induced by CIH is less pronounced than it would be in their absence. In addition to HTN, SA increases the risk of ischemic stroke by ~4 fold. The same PVN adaptations to SA/CIH that participate in development of HTN are hypothesized to reduce ischemic injury by limiting the rise of extracellular L-Glu and reducing the production of neurotoxic NO. Studies in this revised proposal will expose rats to 7 and 28 days of CIH and CIH with hypercapnia (CIHHC) to more closely model human SA. Our specific aims will: (1) Determine effects of CIH & CIHHC on neurogenic HTN, PVN expression of synaptic/excitotoxic signaling proteins and PVN neuronal/tissue survival after local ischemia. (2) Determine effects of CIH/CIHHC adaptations on PVN control of SNA/MAP and mechanisms of neuronal vulnerability to local ischemia. (3) Use viral-mediated gene transfer/shRNA knockdown to mimic and rescue specific PVN adaptations and determine their contributions to hypertensive and neuroprotective effects of CIH & CIHHC.

项目摘要 睡眠呼吸暂停（SA）影响约15％的美国人口。大多数患有SA的人会出现神经源性高血压 （HTN）与交感神经活动升高（SNA）有关。在上一个资金周期中，我们 通过将大鼠暴露于慢性间歇性缺氧（CIH）中进行建模。我们确定HTN诱导 7天的CIH通过夸张的NMDA驱动的交感前PVN神经元排放来维持7天 受体（NMDAR）音调。重要的是，我们发现CIH激活PVN涉及局部自适应 响应（即可塑性），其中神经元NMDAR亚基（Glun1＆Glun2b）的表达降低，并且 神经胶质L-谷氨酸（L-GLU）转运蛋白EEAT2的表达增加。这些反应反映了 对夸张的谷氨酸能输入的稳态改编，我们假设，至少部分出现了 后脑NTS（项目1）和前脑MNPO（项目2）。 CIH还降低了PVN的表达 与NMDAR GLUN2B亚基和神经元氮形成三元复合物的适配器蛋白PSD95 氧化物（NO）合酶（NNOS）。这种复合物将NMDAR CA2+涌入与NO的产生。我们 假设这些对CIH的适应有两个抵消动作。 （1）减少NMDAR并增加 EAAT2表达钝性谷氨酸能PVN激活，从而htn的缓冲液发展。 （2）减少 PSD95钝了NMDAR驱动的无生产，并降低了其对GABA释放的促进性。这是抑制的 PVN及其支持HTN的发展。这些相反的改编的净效应是HTN 由CIH诱导的比在他们缺席的情况下不那么明显。除了HTN，SA还增加了风险 〜4倍的缺血性中风。参与HTN开发的SA/CIH的同一PVN适应 假设可以通过限制细胞外L-GLU的升高并减少缺血性损伤 神经毒性编号的产生。在此修订的建议中的研究将使大鼠暴露于CIH和CIH的7天和28天 与HyperCapnia（CIHHC）更紧密地对人类SA进行建模。我们的具体目的将：（1）确定 CIH和CIHHC在神经源HTN上，突触/兴奋性信号蛋白和PVN的PVN表达 局部缺血后的神经元/组织存活。 （2）确定CIH/CIHHC适应对PVN控制的影响 SNA/MAP和神经元脆弱性与局部缺血的机制。 （3）使用病毒介导的基因 将/shRNA敲低转移到模仿和营救特定的PVN适应，并确定其对 CIH和CIHHC的高血压和神经保护作用。