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

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）是导致神经源性高血压的中枢机制的主要参与者。 Ang II 在大脑内发挥作用，导致血压升高，这种作用涉及的生理机制包括血管紧张素 1 型受体 (AT1-R) 介导的下丘脑室旁核 (PVN) 交感血管舒缩神经元的激活。 PVN 是整合心血管状态信息的关键中继点，通过增加投射到头端腹外侧延髓 (RVLM) 等区域的传出神经活动，引起交感神经流出和血压增加。有大量证据表明，Ang II 的这种中枢作用在神经源性高血压中被放大并导致神经源性高血压。因此，了解 Ang II 如何通过正常动物的大脑调节心血管功能，包括作用和调节机制，对于揭示高血压中枢 Ang II/AT1R 机制持续过度活动的原因以及最终开发新的治疗干预措施至关重要。我们之前确定，在正常大鼠中，MIF 是 Ang II 诱导的细胞内负调节剂，调节 AT1R 介导的 PVN 对 RVLM 交感神经元的兴奋和 Ang II 诱导的升压效应。我们还确定，这种 MIF 调节机制在表现出慢性中枢 AT1R 激活的神经源性高血压动物模型中功能失调，包括自发性高血压大鼠 (SHR)。 当前提案的总体目标是研究 2 型血管紧张素受体 (AT2R) 与 MIF 协同作用，在正常和高血压大鼠的 PVN 处通过 AT1R 调节 Ang II 的心血管作用。该策略基于我们的初步观察，即 Ang II 和 MIF 都会引起 PVN 神经元中 AT2R 表达的显着增加，并且正常血压大鼠 PVN 中 AT2R 水平的增加会减弱 AT1R 介导的对 CNS 注射 Ang II 的升压反应。基于此，我们发表了关于 Ang II 和 MIF 在 PVN 控制血压中的研究，并记录了 AT2R 的神经元抑制作用，我们提出了以下总体假设： (b) SHR 的 PVN 中不存在这种 MIF/AT2R 调节机制，但可以通过增加该位点的 MIF 神经元表达来恢复。这些假设将通过以下目的进行检验：（1）研究MIF对正常血压大鼠和SHR的PVN至RVLM神经元AT2R表达的影响； (2) 确定在 PVN 至 RVLM 神经元中响应 MIF 诱导的 AT2R 是否产生与 AT1R 介导的相同细胞兴奋相反的效应； (3)研究PVN中AT2R在MIF对正常血压大鼠和SHR中Ang II/AT1R诱导的心血管反应的抑制作用中的作用。这些目标将通过多学科（细胞、分子、生理）方法进行研究。