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.

项目概要 睡眠呼吸暂停 (SA) 影响约 15% 的美国人口。大多数 SA 患者会出现神经源性高血压 （HTN）与交感神经活动（SNA）升高相关。在上一个融资周期中，我们 通过将大鼠暴露于慢性间歇性缺氧（CIH）来模拟SA HTN。我们确定 HTN 是由 7 天的 CIH 由夸大的 NMDA 驱动的前交感神经 PVN 神经元放电维持 受体（NMDAR）音调。重要的是，我们发现 CIH 激活 PVN 涉及局部自适应 反应（即可塑性），其中神经元 NMDAR 亚基（GluN1 和 GluN2B）的表达减少，并且 神经胶质 L-谷氨酸 (L-Glu) 转运蛋白 EEAT2 的表达增加。这些回应反映出 对夸大的谷氨酸输入的稳态适应，我们假设至少部分是由 后脑 NTS（项目 1）和前脑 MnPO（项目 2）。 CIH 还降低了 PVN 的表达 衔接蛋白 PSD95，与 NMDAR GluN2B 亚基和神经元硝酸盐形成三元复合物 氧化物（NO）合酶（nNOS）。该复合物将 NMDAR Ca2+ 流入与 NO 产生结合起来。我们 假设这些对 CIH 的适应有两个抵消作用。 (1) NMDAR减少，NMDAR增加 EAAT2 表达减弱谷氨酸能 PVN 激活，从而缓冲 HTN 的发育。 (2)减少 PSD95 会减弱 NMDAR 驱动的 NO 产生，并减弱其对 GABA 释放的促进作用。这会抑制 PVN，从而支持HTN的发展。这些相反的适应的净效应是 HTN CIH 引起的影响不如没有 CIH 时那么明显。除了HTN之外，SA还增加了风险 缺血性中风的发生率增加约 4 倍。参与 HTN 开发的与 SA/CIH 相同的 PVN 改编 假设通过限制细胞外 L-Glu 的升高和减少 产生神经毒性NO。本修订提案中的研究将让大鼠接受 7 天和 28 天的 CIH 和 CIH 与高碳酸血症 (CIHHC) 更接近地模拟人类 SA。我们的具体目标是： (1) 确定 CIH 和 CIHHC 对神经源性 HTN、PVN 突触/兴奋毒性信号蛋白和 PVN 表达的影响 局部缺血后神经元/组织的存活。 (2) 确定 CIH/CIHHC 适应对 PVN 控制的影响 SNA/MAP 和神经元局部缺血脆弱性的机制。 (3)利用病毒介导的基因 转移/shRNA 敲低以模仿和拯救特定的 PVN 适应并确定它们对 CIH 和 CIHHC 的高血压和神经保护作用。