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: 7102601
• 负责人: COLIN SUMNERS
• 金额: $ 49.71万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102601
• 关键词: angiotensin II; bioperiodicity; blood pressure; cardiovascular function; enzyme activity; gene expression; hormone regulation /control mechanism; laboratory rat; migration inhibition factor; neurons; neuroregulation; paraventricular nucleus

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) acts via neuronal Ang II type 1 receptors (AT1-R) within the brain to increase sympathetic outflow and blood pressure, and hyperactivity of these effects plays a major role in hypertension. Thus, factors that regulate the neuronal actions of Ang II in the brain will modify the effects of this peptide on blood pressure. The current proposal focuses on the role of macrophage migration inhibitory factor (MIF) as a possible intracellular regulator of these neuronal actions of Ang II, in particular at the paraventricular nucleus (PVN), a center for control of sympathetic outflow and blood pressure. Based on preliminary findings we have developed the novel hypothesis that MIF, produced within neurons in response to Ang II, acts as a chronic intracellular negative feedback regulator of Ang II's chronotropic actions. Specifically, the proposal is that: (i) In normotensive rat neurons MIF, produced in response to Ang II, exerts an inhibitory influence which dampens or prevents further stimulatory actions of Ang II on neuronal firing; (ii) MIF inhibits the neuronal chronotropic action of Ang II via it's thiol-oxidoreductase activity, scavenging of reactive oxygen species (ROS) and modulation of membrane K+ and Ca2+ currents; (iii) In normotensive rat PVN, Ang ll-induced increases in MIF expression serve to blunt or depress subsequent increases in sympathetic outflow and blood pressure elicited by Ang II. In this proposal our overall goal is to investigate a novel role of MIF as an inhibitor of Ang ll-induced responses in neurons. The above hypotheses will be tested through in vitro and in vivo studies that will combine cellular, molecular, gene transfer and physiological approaches. The specific aims are: (1) Investigate the role of MIF as an inhibitor of the chronotropic action of Ang II in neurons; (2) Investigate the intracellular mechanisms by which MIF affects the neuronal chronotropic actions of Ang II; (3) Determine the consequences of increased MIF expression in the PVN to Ang ll-induced cardiovascular effects. These studies will establish a role for MIF as an inhibitory regulator of the CNS actions of Ang II on sympathetic outflow and blood pressure, and will lay the groundwork for determining whether a lack of this MIF regulatory mechanism contributes to hypertension.

描述(申请人提供)：血管紧张素II(Ang II)通过脑内神经元Ang II 1型受体(AT1-R)增加交感神经流出和血压，这些作用的过度活跃在高血压中起主要作用。因此，调节大脑中血管紧张素II的神经活动的因素将改变这种多肽对血压的影响。目前的建议集中在巨噬细胞移动抑制因子(MIF)作为Ang II这些神经元活动的可能的细胞内调节因子的作用，特别是在控制交感神经流出和血压的中枢-室旁核(PVN)。根据初步发现，我们提出了一个新的假说，即神经元内产生的MIF是Ang II变时性作用的慢性细胞内负反馈调节因子。具体地说，在正常血压的大鼠神经元上，Ang II所产生的MIF对神经元放电产生抑制作用，从而抑制或阻止Ang II对神经元放电的进一步刺激作用；(Ii)MIF通过其硫醇氧化还原酶活性、清除活性氧(ROS)以及膜K+和Ca~(2+)电流的调制来抑制Ang II的神经元变时性作用；(3)在正常血压的大鼠PVN中，AngⅡ诱导的MIF表达的增加可以钝化或抑制Ang II引起的交感神经流出和血压的随后增加。在本研究中，我们的总体目标是研究MIF作为AngⅡ诱导的神经元反应的一种新的抑制作用。上述假设将通过结合细胞、分子、基因转移和生理方法的体外和体内研究进行验证。其具体目的是：(1)研究MIF作为Ang II变时性作用的抑制因子在神经元中的作用；(2)研究MIF影响Ang II变时性作用的细胞内机制；(3)确定MIF在PVN中表达增加对Ang II诱导的心血管效应的影响。这些研究将确立MIF作为Ang II对交感神经流出和血压的中枢神经系统作用的抑制调节因子的作用，并将为确定MIF调节机制的缺失是否导致高血压奠定基础。