Angiotensin-(1-7) engages hypothalamic arcuate-paraventricular nucleus inhibitory pathways to lower blood pressure

血管紧张素-(1-7) 参与下丘脑弓状室旁核抑制通路来降低血压

• 批准号: 10751682
• 负责人: Victoria Lynn Vernail
• 金额: $ 3.45万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751682
• 关键词: Address; Animal Model; Animals; Antihypertensive Agents; Area; Attenuated; Binding; Blood Pressure; Body Weight decreased; Brain; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Clinical; Data; Disease; Electrophysiology (science); Epidemic; Goals; Health; High Fat Diet; Hormones; Hypertension; Hypothalamic structure; Institution; Insulin; Knockout Mice; Measures; Melanocortin 4 Receptor; Mentorship; Metabolic; Methods; Molecular; Mus; Neurons; Neurosciences; Neurosciences Research; Neurotransmitters; Obese Mice; Obesity; Obesity Related Hypertension; Pathway interactions; Peripheral; Pharmaceutical Preparations; Physiological; Pro-Opiomelanocortin; Receptor Signaling; Regulation; Renin-Angiotensin System; Research; Research Personnel; Rest; Risk; Rodent; Saline; Signal Pathway; Signal Transduction; Structure of nucleus infundibularis hypothalami; Testing; Tissues; Transgenic Mice; Work; angiotensin I (1-7); antagonist; blood pressure elevation; blood pressure reduction; career; clinically relevant; comparison control; diet-induced obesity; dietary control; experimental study; gamma-Aminobutyric Acid; hypertension treatment; hypertensive; improved; innovation; insight; insulin sensitivity; lipid metabolism; metabolic profile; mouse model; neural circuit; neuromechanism; neurotransmission; new therapeutic target; novel; obesity treatment; optimal treatments; paraventricular nucleus; patch clamp; patient population; pharmacologic; presynaptic; prevent; receptor; response; side effect; skills; therapeutic target; transmission process; treatment comparison; treatment guidelines; treatment strategy

PROJECT SUMMARY Obesity is a global epidemic that greatly increases the risk for developing hypertension and cardiovascular disease. The molecular mechanisms connecting hypertension with obesity are poorly understood, however, and optimal treatment strategies are unclear as some antihypertensive drugs elicit adverse metabolic side effects. This illustrates the critical need to identify new therapeutic targets with a positive metabolic profile for treatment of obesity hypertension. We propose that angiotensin (Ang)-(1-7), a protective hormone of the renin- angiotensin system, provides this ideal target. Ang-(1-7) binds mas receptors (masR) to lower blood pressure and improve metabolic function in obese and hypertensive rodents; but the mechanisms involved are unknown. Our preliminary data show that Ang-(1-7) depressor effects require activation of masR within the arcuate nucleus of the hypothalamus (ARC). More specifically, we show that Ang-(1-7) masR are highly localized to proopiomelanocortin (POMC)-containing neurons that release the inhibitory neurotransmitter GABA. Activation of GABAergic POMC neurons by Ang-(1-7) could lower blood pressure by inhibiting downstream melanocortin-4 receptor (MC4R) signaling in the hypothalamic paraventricular nucleus (PVN), but this has not been explored. This proposal will test the central hypothesis that Ang-(1-7) stimulates ARC POMC neurons to enhance GABAergic neurotransmission onto PVN neurons to lower blood pressure. Aim 1 will determine if POMC masR are required for Ang-(1-7) to inhibit PVN neuronal activity and lower blood pressure. To test this, we will employ a novel transgenic mouse model to determine if deletion of masR from POMC neurons prevents the ability of Ang-(1-7) to enhance GABAergic activity in the PVN and lower blood pressure under normal conditions and in the context of high fat diet-induced obesity hypertension. Aim 2 will determine if high fat diet decreases, and Ang-(1-7) treatment restores, GABAergic transmission onto MC4R-expressing PVN neurons. To test this, we will employ MC4R-GFP mice to determine if: high fat diet decreases inhibitory neurotransmission in MC4R-expressing PVN neurons, Ang-(1-7) treatment reverses these effects, and changes in inhibitory neurotransmission in MC4R-PVN neurons correlate with blood pressure. The findings from this proposal will provide new insight into the neural mechanisms by which Ang-(1-7) lowers blood pressure as well as the potential for therapeutic targeting of Ang-(1-7) in obesity hypertension. Importantly, this proposal will logically build upon the PI’s background in molecular neuroscience and allow her to develop a new skillset in integrated molecular and whole animal physiological and pharmacological methods to assess neural mechanisms engaged by Ang-(1-7) for cardiovascular regulation. The PI will receive strong mentorship and a research framework to establish an independent and novel area of research to help meet her long-term career goal of becoming an independent investigator at an academic research institution where she can conduct collaborative and clinically relevant cardiovascular neuroscience research.

项目摘要 肥胖是一种全球流行病，它大大增加了患高血压和心血管疾病的风险。 疾病然而，人们对高血压与肥胖之间的分子机制知之甚少， 最佳治疗策略尚不清楚，因为一些抗高血压药物会引起不良代谢副作用 方面的影响.这说明迫切需要确定新的治疗靶点，具有积极的代谢特征， 治疗肥胖高血压。我们认为，血管紧张素（Ang）-（1-7），一种保护肾素-血管紧张素受体的激素， 血管紧张素系统，提供了这个理想的目标。Ang-（1-7）结合mas受体（masR）降低血压 并改善肥胖和高血压啮齿动物的代谢功能;但涉及的机制是 未知我们的初步数据表明，Ang-（1-7）的降压作用需要激活血管内皮细胞内的masR。 下丘脑弓状核（ARC）。更具体地说，我们表明Ang-（1-7）masR是高表达的。 定位于释放抑制性神经递质的含阿黑皮素原（POMC）的神经元 GABA Ang-（1-7）激活GABA能POMC神经元可通过抑制血压升高来降低血压 下游黑皮质素-4受体（MC 4 R）信号传导在下丘脑室旁核（PVN），但 这一点尚未得到探讨。该提议将检验Ang-（1-7）刺激ARC POMC的中心假设 神经元增强GABA能神经传递到PVN神经元以降低血压。目标1将 确定POMC masR是否是Ang-（1-7）抑制PVN神经元活性和降低血压所必需的。 为了测试这一点，我们将采用一种新型转基因小鼠模型来确定是否从POMC中缺失masR 神经元阻止Ang-（1-7）增强PVN中GABA能活性和降低血压的能力 在正常条件下和在高脂肪饮食引起的肥胖高血压的情况下。目标2将确定是否 高脂饮食减少，Ang-（1-7）治疗恢复GABA能传递至表达MC 4 R的细胞， PVN神经元。为了测试这一点，我们将使用MC 4 R-GFP小鼠来确定是否： 在MC 4 R表达PVN神经元的神经传递中，Ang-（1-7）治疗逆转了这些作用， MC 4 R-PVN神经元中抑制性神经传递的变化与血压相关。这些发现 从这个建议将提供新的洞察神经机制，其中血管紧张素-（1-7）降低血液 以及Ang-（1-7）在肥胖高血压中的治疗靶向潜力。重要的是这 该提案将在逻辑上建立在PI的分子神经科学背景之上，并允许她开发一个 在综合分子和整体动物生理学和药理学方法的新技能，以评估 Ang-（1-7）参与心血管调节的神经机制。PI将获得强大的指导 和一个研究框架，以建立一个独立和新颖的研究领域，以帮助满足她的长期 职业目标是成为一个独立的研究人员在学术研究机构，在那里她可以 开展协作和临床相关的心血管神经科学研究。