Contribution of Orexin System to Hypertension

食欲素系统对高血压的贡献

• 批准号: 10609506
• 负责人: Zhiying Shan
• 金额: $ 43.92万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609506
• 关键词: Accounting; Adrenal Glands; Animal Model; Area; Arousal; Attenuated; Automobile Driving; Binding; Biochemical; Blood Pressure; Brain; Brain region; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cells; Central Nervous System; Chronic; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Cytokine Signaling; Data; Development; Disease; Electrophysiology (science); Etiology; Extracellular Signal Regulated Kinases; Gene Expression; Genetic; Genetic Transcription; Growth; Hormones; Human; Hyperactivity; Hypertension; Hypothalamic structure; Impairment; Inbred Dahl Rats; Inbred SHR Rats; Inflammation; Inflammatory; Injections; Intake; Lateral; Lesion; MAPK3 gene; Maintenance; Mediating; Modeling; Molecular; Nerve; Neuroendocrine Cell; Neurons; Neuropeptides; Neurosecretory Systems; Obesity; Outcome; Phosphorylation; Physiological; Pituitary Gland; Plasma; Play; Production; Rattus; Receptor Activation; Receptor Signaling; Regulation; Resistance; Rewards; Risk Factors; Role; Saline; Signal Induction; Signal Pathway; Signal Transduction; Social Impacts; Sodium Chloride; Sprague-Dawley Rats; Stress; System; TNF gene; Testing; Therapeutic Intervention; Transduction Gene; United States; Up-Regulation; Vasopressins; Zucker Rats; antagonist; blood pressure reduction; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; combat; cytokine; economic impact; feeding; high salt diet; hormonal signals; human model; hypertension treatment; hypertensive; hypocretin; hypothalamic-pituitary-adrenal axis; in vivo; knock-down; mRNA Expression; mind control; neurochemistry; neurotransmission; new therapeutic target; normotensive; orexin 1 receptor; orexin A; orexin B; overexpression; paraventricular nucleus; prevent; receptor; receptor expression; response; salt intake; salt sensitive; salt sensitive hypertension

SUMMARY Hypertension is a major risk factor for cardiovascular disease, with salt sensitive hypertension (SSH) accounting for 51% of all cases. As augmented sympathetic nerve activity (SNA) and dysregulated neuroendocrine secretion are known to play critical roles in the development of SSH, w e propose a study to investigate the mechanisms whereby hyperactivity of the brain orexin system, may critically influence SNA and neuroendocrine dysregulation, thus contributing to SSH development. Orexin A (OXA) is a multifunctional neuropeptide produced by hypothalamic neurons that plays various physiological roles, including cardiovascular function, through binding with its receptors. Recent studies show that upregulation of brain orexin signaling occurs in several animal models of hypertension suggesting implications for overactive brain orexin signaling in hypertension development. However, the impact of orexin system in the development of SSH and detailed molecular mechanisms underlying orexin system mediated hypertension development are poorly understood. Our preliminary data shows that a high salt (HS) diet results in hypertension, and significantly increases expression of OXA and orexin 1 receptor (OX1R) in the hypothalamic paraventricular nucleus (PVN) of Dahl salt sensitive (Dahl S) rats, an animal model for human SSH, but not in salt resistant rats. Interestingly, HS diet intake in Dahl S rats also increases OX1R expression in adrenal glands, a component of hypothalamic-pituitary- adrenal (HPA) axis which is a central neuroendocrine response system to combat stress and regulate multiple physiological functions. The PVN controls SNA outflow and neuroendocrine hormone, such as vasopressin (AVP) and corticotropin-releasing hormone (CRH), production. Central administration of OXA increases SNA outflow and PVN AVP expression as well as plasma corticosterone levels, a hallmark of HPA axis activation. Hyperactivity of HPA axis is involved in multiple diseases including hypertension. Lesions in the PVN prevent high salt induced hypertension in Dahl S rats. This body of evidence suggests that PVN OX1R activation is involved in SNA and HPA axis regulation, and increased PVN OXA-OX1R signaling induced by high salt intake may stimulate neuroendocrine systemic secretion, trigger long-term adaptive changes through regulating downstream gene expression, producing excessive excitatory neurochemicals, resulting in augmented PVN sympathetic tone, and leading to SSH. The objectives of this project are: (i) investigate whether chronic knockdown of PVN OX1R expression decreases plasma corticosterone levels, attenuate HS induced increase in SNA, and prevent SSH; (ii) elucidate the molecular mechanism underlying the relationship between OXA-OX1R and its augmentation of SNA and dysregulation of HPA axis. A combination of in vivo gene transduction, electrophysiological recordings, and molecular and biochemical approaches will be employed to answer our questions using salt sensitive and normotensive rat models. Our studies may identify new targets for therapeutic intervention in hypertension.

概括 高血压是心血管疾病的主要危险因素，其中盐敏感性高血压（SSH） 占全部病例的51%。由于交感神经活动（SNA）增强且失调 众所周知，神经内分泌分泌在 SSH 的发展中发挥着关键作用，我们提出了一项研究 研究大脑食欲素系统过度活跃可能严重影响 SNA 的机制 和神经内分泌失调，从而促进 SSH 的发展。 食欲素 A (OXA) 是一种由下丘脑神经元产生的多功能神经肽，具有多种作用 通过与其受体结合发挥生理作用，包括心血管功能。最近的研究表明 在几种高血压动物模型中，大脑食欲素信号传导上调，这表明 大脑食欲素信号过度活跃对高血压发展的影响。然而，食欲素的影响 SSH 发展中的系统以及食欲素系统介导的详细分子机制 人们对高血压的发展知之甚少。我们的初步数据显示，高盐 (HS) 饮食会导致 高血压中，并显着增加 OXA 和食欲素 1 受体 (OX1R) 的表达 Dahl 盐敏感 (Dahl S) 大鼠的下丘脑室旁核 (PVN)，人类动物模型 SSH，但不适用于耐盐大鼠。有趣的是，Dahl S 大鼠的 HS 饮食摄入也会增加 OX1R 表达 在肾上腺中，下丘脑-垂体-肾上腺 (HPA) 轴的一个组成部分，是中枢神经内分泌 对抗压力和调节多种生理功能的反应系统。 PVN 控制 SNA 流出 和神经内分泌激素，例如加压素（AVP）和促肾上腺皮质激素释放激素（CRH）， 生产。 OXA 的中央给药可增加 SNA 流出、PVN AVP 表达以及血浆 皮质酮水平是 HPA 轴激活的标志。 HPA 轴过度活跃涉及多种 疾病包括高血压。 PVN 损伤可预防 Dahl S 大鼠中高盐诱发的高血压。 这些证据表明 PVN OX1R 激活参与 SNA 和 HPA 轴调节，并且 高盐摄入诱导的 PVN OXA-OX1R 信号增加可能会刺激系统神经内分泌 分泌，通过调节下游基因表达触发长期适应性变化，产生 过量的兴奋性神经化学物质，导致 PVN 交感神经张力增强，并导致 SSH。这 该项目的目标是：(i) 研究 PVN OX1R 表达的慢性敲低是否会降低 血浆皮质酮水平，减弱 HS 诱导的 SNA 增加，并预防 SSH； (二) 阐明 OXA-OX1R 及其增强 SNA 和 SNA 之间关系的分子机制 HPA 轴失调。体内基因转导、电生理记录和 将采用分子和生化方法来回答我们的问题，使用盐敏感和 正常血压大鼠模型。我们的研究可能会确定高血压治疗干预的新目标。