MIF: A novel CNS regulator of cardiovascular function

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枢机制的主要参与者。 血管紧张素II在脑内起作用以增加血压，并且参与该作用的生理机制包括血管紧张素1型受体（AT 1-R）介导的下丘脑室旁核（PVN）处的交感血管神经元的激活。PVN是整合心血管状态信息的关键中继点，通过增加投射到延髓头端腹外侧区（RVLM）等区域的传出神经活动，可显著增加交感神经流出和血压。大量证据表明，血管紧张素II的这种中枢作用在神经源性高血压中被放大并促成神经源性高血压。因此，了解血管紧张素II如何调节心血管功能，通过正常动物的大脑，包括作用和调节机制，是至关重要的，并揭示了中央血管紧张素II/AT 1 R机制在高血压持续过度活动的原因，并最终开发新的治疗干预措施。我们先前已经证实，在正常大鼠中，MIF是一种Ang II诱导的细胞内负性调节剂，它介导AT 1 R对RVLM交感神经元的PVN兴奋和Ang II诱导的升压效应。我们还确定，这种MIF调节机制是功能失调的神经源性高血压的动物模型，表现出慢性中枢AT 1 R激活，包括自发性高血压大鼠（SHR）。 目前的建议的广泛目标是研究血管紧张素2型受体（AT 2 R）的作用，在音乐会与MIF，在调节血管紧张素II通过AT 1 R在PVN在正常和高血压大鼠的心血管活动。这一策略是基于我们的初步观察，即Ang II和MIF引起室旁核神经元中AT 2 R表达的显著增加，并且正常大鼠室旁核中AT 2 R水平的增加减弱了CNS注射Ang II引起的AT 1 R介导的升压反应。在此基础上，我们发表了关于Ang Ⅱ和MIF在PVN控制血压中的作用的研究，并证明了AT 2 R的神经抑制作用，我们提出了以下总体假设：（a）MIF诱导PVN至RVLM神经元中功能性内源性AT 2 R的表达是该蛋白对Ang Ⅱ/AT 1 R心血管作用的长期负调节的关键因素;（B）这种MIF/AT 2 R调节机制在SHR的PVN中不存在，但可以通过在该部位增加的MIF神经元表达来恢复。本研究的目的是：（1）研究MIF对正常大鼠和SHR PVN至RVLM神经元AT_2 R表达的影响，（2）确定MIF在PVN至RVLM神经元中诱导的AT_2 R是否对AT_1 R介导的兴奋产生拮抗作用;（3）探讨室旁核AT 2 R在MIF抑制Ang Ⅱ/AT 1 R诱导的正常血压大鼠和SHR心血管反应中的作用。这些目标将通过多学科（细胞，分子，生理）的方法进行研究。 公共卫生相关性：从最广泛的意义上说，我们的研究旨在了解中枢神经系统（CNS）如何控制健康个体的血压，以及这些控制机制中的故障如何导致高血压。 我们已经确定了大脑中的巨噬细胞迁移抑制因子作为一种调节剂，有助于控制血压并阻止其超过正常范围。拟议研究的直接目标是确定巨噬细胞迁移抑制因子如何与CNS中的血管紧张素2型受体协同作用，以帮助在正常条件下调节血压，以及这种调节在高血压中是否失败。从这些研究中获得的信息可能会导致开发新的高血压治疗靶点。

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. PUBLIC HEALTH RELEVANCE: In the broadest sense our research is aimed at understanding how the central nervous system (CNS) controls blood pressure in healthy individuals, and how faults in these control mechanisms contribute to hypertension. We have identified macrophage migration inhibitory factor in the brain as a regulator that helps to keep blood pressure in check and stop it from exceeding normal limits. The immediate goal of the proposed studies is to determine how macrophage migration inhibitory factor works in concert with angiotensin type 2 receptors in the CNS to help regulate blood pressure under normal conditions, and whether this regulation fails in hypertension. Information gained from these studies may lead to the development of novel therapeutic targets for hypertension.