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.

总结 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） 占所有病例的51%。由于交感神经活动（SNA）增强和失调 已知神经内分泌在SSH的发展中起关键作用，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，从而有助于SSH的发展。 食欲素A（Orexin A，OXA）是由下丘脑神经元产生的多功能神经肽， 生理作用，包括心血管功能，通过与其受体结合。最近的研究表明 在几种高血压动物模型中，大脑食欲素信号的上调表明 过度活跃的大脑食欲素信号在高血压发展中的意义。然而，增食欲素的影响 系统在SSH发展中的作用以及食欲素系统介导的详细分子机制 对高血压发展知之甚少。我们的初步数据表明，高盐（HS）饮食的结果， 在高血压中，OXA和食欲素1受体（OX 1 R）的表达显著增加， Dahl盐敏感大鼠下丘脑室旁核（PVN） SSH，但不耐盐大鼠。有趣的是，在Dahl S大鼠中HS饮食摄入也增加了OX 1 R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 反应系统对抗压力和调节多种生理功能。PVN控制SNA流出 和神经内分泌激素，如加压素（AVP）和促肾上腺皮质激素释放激素（CRH）， 生产OXA的中枢给药增加SNA流出和PVN AVP表达以及血浆 皮质酮水平，HPA轴激活的标志。下丘脑-垂体-肾上腺轴的过度活跃涉及多种 包括高血压在内的疾病。室旁核病变可预防Dahl S大鼠高盐诱导的高血压。 这些证据表明PVN OX 1 R激活参与SNA和HPA轴调节， 高盐摄入诱导的PVN OXA-OX 1 R信号传导增加可能刺激神经内分泌系统 分泌，通过调节下游基因表达触发长期适应性变化， 过度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。的 本项目的目的是：（i）研究PVN OX 1 R表达的慢性敲低是否降低 血浆皮质酮水平，减弱HS诱导的SNA增加，并防止SSH;（ii）阐明 OXA-OX 1 R与其增强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 分子和生物化学的方法将被用来回答我们的问题，使用盐敏感和 血压正常的大鼠模型。我们的研究可能为高血压的治疗干预确定新的靶点。