MIF: A novel CNS regulator of cardiovascular function

说明(申请人提供)：血管紧张素II(Ang II)是神经源性高血压的中枢机制的主要参与者。血管紧张素Ⅱ在脑内起升压作用，其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)交感血管运动神经元的激活。室旁核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)的传出活动，引起交感神经流出增加和血压增加。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参与了神经源性高血压的发生。因此，了解Ang II如何通过脑调节正常动物的心血管功能，包括作用机制和调节机制，对于揭示高血压患者中枢Ang II/AT1R机制持续过度活动的原因，最终开发新的治疗干预措施，具有至关重要的意义。我们先前证实，在正常大鼠中，MIF是血管紧张素Ⅱ诱导的细胞内负调节因子，参与AT1R介导的PVN对RVLM交感神经元的兴奋和血管紧张素Ⅱ诱导的升压效应。我们还确定，在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，这些动物模型表现出慢性中枢AT1R激活，包括自发性高血压大鼠(SHR)。本研究的主要目的是研究血管紧张素2型受体(AT2R)与MIF协同作用，通过AT1R在正常大鼠和高血压大鼠室旁核调节Ang II的心血管作用。这一策略是基于我们的初步观察，即Ang II和MIF都能引起PVN神经元AT2R表达的显著增加，而正常血压大鼠PVN中AT2R水平的增加减弱了AT1R介导的对CNS注射Ang II的升压反应。在此基础上，我们发表了Ang II和MIF在PVN控制血压中的工作，并记录了AT2R的神经元抑制作用。我们提出了以下总体假设：(A)MIF诱导PVN内源性AT2R对RVLM神经元的功能性表达是该蛋白对Ang II/AT1R心血管作用的长期负调节的关键因素；(B)这种MIF/AT2R调控机制在SHR的PVN中缺失，但可通过MIF在该部位神经元表达的增加而恢复。这些假说将通过下列目的得到验证：(1)观察MIF对正常血压大鼠和SHR RVLM神经元PVN中AT2R表达的影响；(2)确定MIF诱导的PVN对RVLM神经元的AT2R是否产生与AT1R介导的相同细胞兴奋具有拮抗作用的效应；(3)探讨MIF在MIF抑制Ang II/AT1R诱导的心血管反应中在PVN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。 与公共健康相关：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缺陷如何导致高血压。我们已经确认大脑中的巨噬细胞移动抑制因子是一种调节因子，有助于控制血压并阻止其超过正常限度。拟议中的研究的直接目标是确定巨噬细胞移动抑制因子如何与中枢神经系统中的血管紧张素2型受体协同工作，以帮助在正常情况下调节血压，以及这种调节是否在高血压中失败。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.