MIF: A novel CNS regulator of cardiovascular function

MIF：心血管功能的新型中枢神经系统调节剂

• 批准号: 8447494
• 负责人: COLIN SUMNERS
• 金额: $ 34.87万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447494
• 关键词: Adult; Angiotensin II; Angiotensins; Animal Model; Animals; Area; Blood Pressure; Brain; Cardiovascular Physiology; Cardiovascular system; Cells; Chronic; Data; Development; Efferent Pathways; Elements; Exhibits; Funding; Goals; Health; Hypertension; Hypothalamic structure; Inbred SHR Rats; Individual; Infusion procedures; Lead; Mediating; Messenger RNA; Migration Inhibitory Factor; Molecular; Neuraxis; Neurons; Oxidoreductase; Participant; Peptides; Physiological; Proteins; Publishing; Rattus; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Regulation; Research; Role; Signal Pathway; Site; Spinal Cord Column; Sulfhydryl Compounds; Testing; Type 2 Angiotensin II Receptor; Vasomotor; Viral Vector; Work; base; blood pressure regulation; factor A; multidisciplinary; neurogenic hypertension; neuromechanism; new therapeutic target; normotensive; novel; novel therapeutic intervention; paraventricular nucleus; phenylpyruvate tautomerase; public health relevance; receptor; receptor expression; response; small hairpin RNA; Adult; Angiotensin II; Angiotensins; Animal Model; Animals; Area; Blood Pressure; Brain; Cardiovascular Physiology; Cardiovascular system; Cells; Chronic; Data; Development; Efferent Pathways; Elements; Exhibits; Funding; Goals; Health; Hypertension; Hypothalamic structure; Inbred SHR Rats; Individual; Infusion procedures; Lead; Mediating; Messenger RNA; Migration Inhibitory Factor; Molecular; Neuraxis; Neurons; Oxidoreductase; Participant; Peptides; Physiological; Proteins; Publishing; Rattus; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Regulation; Research; Role; Signal Pathway; Site; Spinal Cord Column; Sulfhydryl Compounds; Testing; Type 2 Angiotensin II Receptor; Vasomotor; Viral Vector; Work; base; blood pressure regulation; factor A; multidisciplinary; neurogenic hypertension; neuromechanism; new therapeutic target; normotensive; novel; novel therapeutic intervention; paraventricular nucleus; phenylpyruvate tautomerase; public health relevance; receptor; receptor expression; response; small hairpin RNA

DESCRIPTION (provided by applicant): The peptide angiotensin II (Ang II) is known to be a major participant in the central mechanisms that are responsible for neurogenic hypertension. Ang II acts within the brain to increase blood pressure, and the physiological mechanisms involved in this effect include angiotensin type 1 receptor (AT1-R)-mediated activation of sympathetic vasomotor neurons at the paraventricular nucleus of the hypothalamus (PVN). The PVN is a key relay point for integrating information on cardiovascular status and elicits increased sympathetic outflow and blood pressure, via increases in the activity of efferents projecting to areas such as the rostral ventrolateral medulla (RVLM). There is much evidence that this central action of Ang II is amplified in and contributes to neurogenic hypertension. Thus, understanding how Ang II regulates cardiovascular function via the brain in normal animals, including mechanisms of action and regulation, is critical and highly significant to uncovering the reasons for persistent over activity of central Ang II/AT1R mechanisms in high blood pressure and ultimately to the development of new therapeutic interventions. We established previously that in normal rats MIF is an Ang II-inducible intracellular negative regulator of the AT1R mediated excitation of PVN to RVLM sympathetic neurons and Ang II-induced pressor effect. We also determined that this MIF regulatory mechanism is dysfunctional in animal models of neurogenic hypertension that exhibit chronic central AT1R activation, including spontaneously hypertensive rats (SHR). The broad goal of the current proposal is to investigate the role of angiotensin type 2 receptors (AT2R), in concert with MIF, in regulating the cardiovascular actions of Ang II via AT1R at the PVN in normal and hypertensive rats. This strategy is based on our preliminary observations that both Ang II and MIF elicit profound increases in the expression of AT2R in PVN neurons, and that increased levels of AT2R in normotensive rat PVN blunts the AT1R-mediated pressor response to CNS-injected Ang II. Based on this, our published work on Ang II and MIF in the PVN control of blood pressure, and documented neuronal inhibitory actions of AT2R we developed the following overall hypotheses: (a) MIF induced expression of functional endogenous AT2R in PVN to RVLM neurons is a critical element of the longer term negative regulation by this protein over Ang II/AT1R cardiovascular actions; (b) This MIF/AT2R regulatory mechanism is absent from the PVN of SHR, but can be restored by the increased neuronal expression of MIF at this site. These hypotheses will be tested via the following aims: (1) Investigate the effects of MIF on AT2R expression in PVN to RVLM neurons of normotensive rats and SHR; (2) Determine whether AT2R, induced in PVN to RVLM neurons in response to MIF, produce effects that are antagonistic to AT1R-mediated excitation of the same cells; (3) Investigate the role of AT2R in the PVN in the inhibitory effects of MIF over Ang II/AT1R-induced cardiovascular responses in normotensive rats and SHR. These aims will be studied through a multidisciplinary (cellular, molecular, physiological) approach.

描述（由申请人提供）：已知肽血管紧张素II（ANG II）是负责神经源性高血压的中心机制的主要参与者。 ANG II起作用在大脑内增加血压，并且这种作用涉及的生理机制包括血管紧张素1型受体（AT1-R）介导的副作用血管肌舒米神经元在下丘脑（PVN）的旁腔内核的激活。 PVN是整合有关心血管状态的信息的关键继电器，并通过增加投射到诸如the Rostral腹侧延髓（RVLM）等区域的活动的活动来增加交感神经流出和血压。有很多证据表明，ANG II的中心作用被放大并有助于神经源性高血压。因此，了解ANG II如何通过正常动物中的大脑调节心血管功能，包括作用和调节机制，对于揭示高血压中中央ANG II/AT1R机制的持续活动的原因至关重要，并且最终对新的治疗干预的发展而言。我们先前确定在正常大鼠中，MIF是ANG II诱导的细胞内负调节剂，其PVN对RVLM交感神经元和ANG II诱导的施加效应的AT1R介导的激发剂的激发。我们还确定，在表现出慢性中央AT1R激活的神经源性高血压动物模型中，这种MIF调节机制是功能失调的，包括自发性高血压大鼠（SHR）。 当前提案的广泛目标是研究与MIF一起调节ANG II通过AT1R在正常和高血压大鼠中的ANG II通过AT1R的心血管作用来研究血管紧张素2型受体（AT2R）的作用。该策略是基于我们的初步观察结果，即ANG II和MIF都会引起PVN神经元中AT2R表达的深刻增加，并且在正常的大鼠PVN中，AT2R的水平升高，使AT1R介导的压力器对CNS注入的ANG II的反应呈现。基于这一点，我们在PVN控制血压中发表了有关ANG II和MIF的发表工作，并记录了AT2R的神经元抑制作用，我们开发了以下总体假设：（a）MIF诱导PVN中功能性内源性AT2R对RVLM神经元的功能性内源性表达，这是该蛋白质超过Angai的长期负元素的关键元素。 （b）SHR的PVN不存在这种MIF/AT2R调节机制，但可以通过该部位的MIF的神经元表达恢复。这些假设将通过以下目的进行检验：（1）研究MIF对PVN中AT2R表达对正常大鼠和SHR的RVLM神经元的影响； （2）确定在PVN中诱导RVLM神经元的AT2R是否响应MIF产生与AT1R介导的同一细胞激发拮抗的作用； （3）研究AT2R在PVN中的作用在MIF对正常大鼠和SHR中ANG II/AT1R诱导的心血管反应的抑制作用中。这些目标将通过多学科（细胞，分子，生理）方法进行研究。