Ang II and Norepinephrine in Cardiac Sympathetic Nerves

心脏交感神经中的 Ang II 和去甲肾上腺素

基本信息

批准号：
7567590
负责人：
ROBERTO LEVI
金额：
$ 39.82万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7567590
关键词：
1-Methyl-4-phenylpyridinium 6-carboxyfluorescein ANG gene Abbreviations Acute Address Amiloride Angiotensin I Angiotensin II Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Arrhythmia Biological Buffers Calcium Calmodulin Cardiac Cavia Cell Degranulation Cell Line Cell model Cells Cessation of life Chemosensitization Coupling Cultured Cells Data Desipramine Elements Enzymes Esters Exocytosis Exposure to Figs - dietary Functional disorder Grant Heart Human Incubated Investigation Ischemia Kidney Knock-out Knockout Mice Measures Mediating Membrane Modeling Molecular Mus Myocardial Ischemia Nerve Nerve Endings Neuroblastoma Neurons Norepinephrine Parents Pathologic Pathway interactions Peptidyl-Dipeptidase A Physiological Physiology Play Proto-Oncogene Protein c-kit Rattus Receptor, Angiotensin, Type 1 Renin Renin-Angiotensin System Reperfusion Therapy Research Personnel Role Signal Pathway Signal Transduction Source Synaptosomes Ventricular Fibrillation Work base congenic mast cell noradrenaline transporter novel paracrine prevent programs receptor research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): In myocardial ischemia, pathologic release of norepinephrine (NE) from sympathetic nerves leads to arrhythmias and death. The mechanisms responsible remain obscure. The overall objective of this grant is to address the important biological issue of whether a local renin-angiotensin system (RAS) plays a significant role in exacerbating NE release in myocardial ischemia. Our preliminary results demonstrate that cardiac mast cells are a novel source of renin, the rate-limiting enzyme responsible for initiating ANG n formation. We hypothesize that degranulation of cardiac mast cells, as occurs in ischemia, is pivotal for activation of local RAS and ANG II formation in the proximity of neuronal ATi receptors (ATiR). In Specific Aim I, we will characterize mast-cell renin from congenic controls (CC) of c-Kit knock out (KO) mice, and from cultured human mast cells (HMC-1). We will also investigate in normoxic and ischemic cardiac models from guinea-pigs, and CC and KO mice, whether locally synthesized ANG n from mast-cell-derived renin activates neuronal ATiR to elicit NE release and reperfusion arrhythmias. We have already ascertained in a cultured-cell model of ischemic sympathetic nerves, that exogenous ANG n stimulates neuronal Na+/H^ exchange (NHE) leading to excessive carrier-mediated NE release. Thus, in Specific Aim n we will study, in human neuroblastoma cells transfected with the cloned rat ATjA receptor (SH-SYSY-ATu), the signal transduction of this ANG H-mediated NHE stimulation. Experiments in SH-SYSY-ATiA cells demonstrate that stimulation of NHE and carrier-mediated NE release by AT)R activation occurs via a Ca +-dependent pathway. Accordingly, our investigation will focus on elucidating the role of PLC, Ca2+, PKC, and calmodulin in this Ca2+-dependent pathway. The overall premise of these experiments is that if we understand the patho-physiological basis for the formation of ANG n in the ischemic heart, and how ANG II exacerbates NE release, then we will also have identified potential therapeutic targets to alleviate ischemic arrhythmias and associated cardiac dysfunctions.

描述（由申请人提供）：在心肌缺血中，从交感神经中去甲肾上腺素（NE）的病理释放导致心律不齐和死亡。负责的机制仍然晦涩难懂。该赠款的总体目的是解决重要的生物学问题，即局部肾素 - 血管紧张素系统（RAS）是否在加剧心肌缺血中释放NE中发挥重要作用。我们的初步结果表明，心脏肥大细胞是肾素的新来源，肾素是限制的酶，负责启动ANG N形成。我们假设在缺血中发生的心脏肥大细胞的脱粒是在神经元ATI受体（ATIR）接近局部RAS和ANG II形成的关键。在特定的目标I中，我们将表征来自C-KIT敲除（KO）小鼠的先天性对照（CC）的肥大细胞肾素，以及来自培养的人类肥大细胞（HMC-1）。我们还将在豚鼠的常氧和缺血性心脏模型中调查，以及CC和KO小鼠，无论是从肥大细胞衍生的肾素中局部合成的ANG N是否会激活神经元atir以引起NE释放和再灌注心律失常。我们已经在缺血性交感神经的培养细胞模型中确定，外源ANG N刺激神经元Na+/H^交换（NHE）导致过度载体介导的NE释放。因此，在特定目标中，我们将研究用克隆大鼠ATJA受体（SH-SYSY-ATU）转染的人神经母细胞瘤细胞，该ANG H-介导的NHE刺激的信号转导。 SH-SY-ATIA细胞中的实验表明，AT激活对NHE和载体介导的NE释放的刺激是通过CA +依赖性途径发生的。因此，我们的研究将集中于阐明PLC，Ca2+，PKC和钙调蛋白在CA2+依赖性途径中的作用。这些实验的总体前提是，如果我们了解缺血性心脏中ANG N的病理生理基础，以及ANG II如何加剧NE的释放，那么我们还将确定潜在的治疗靶标，以减轻缺血性心律失常和相关的心脏功能障碍。