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

• 批准号: 7383071
• 负责人: ROBERTO LEVI
• 金额: $ 47.79万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383071
• 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; Physiological reperfusion; Physiology; Play; Proto-Oncogene Protein c-kit; Rate; Rattus; Receptor, Angiotensin, Type 1; Renin; Renin-Angiotensin System; Reperfusion Therapy; Research Personnel; Role; Signal Pathway; Signal Transduction; Source; Synaptosomes; Ventricular Fibrillation; Work; angiogenin; base; congenic; mast cell; noradrenaline transporter; novel; paracrine; prevent; programs; receptor; research study; response; therapeutic target

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，交感神经病理性释放去甲肾上腺素（NE）导致心律失常和死亡。 对此负责的机制仍不清楚。 这项研究的总体目标是解决局部肾素-血管紧张素系统（RAS）是否在心肌缺血时加剧NE释放中起重要作用的重要生物学问题。 我们的初步结果表明，心脏肥大细胞是一种新的来源，肾素，限速酶负责启动血管紧张素n的形成。 我们推测，心肌肥大细胞的脱粒，如缺血发生，是关键的激活局部RAS和ANG II形成的神经元ATi受体（ATiR）附近。 在特定目标I中，我们将从c-Kit敲除（KO）小鼠的同类对照（CC）和培养的人肥大细胞（HMC-1）中表征肥大细胞肾素。 我们还将研究在正常氧和缺血心脏模型，从豚鼠，CC和KO小鼠，是否本地合成的ANG n从肥大细胞来源的肾素激活神经元ATiR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，外源性ANG n刺激神经元Na+/H+交换（NHE），导致过度的载体介导的NE释放。 因此，在特定目标n中，我们将研究在用克隆的大鼠ATjA受体（SH-SYSY-ATu）转染的人神经母细胞瘤细胞中，这种ANG H介导的NHE刺激的信号转导。 在SH-SYSY-ATiA细胞中的实验证明，通过AT）R活化对NHE和载体介导的NE释放的刺激经由Ca +依赖性途径发生。 因此，我们的研究将集中在阐明PLC，Ca 2+，PKC和钙调素在这一Ca 2+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形成的病理生理学基础，以及ANG II如何加剧NE释放，那么我们也将确定潜在的治疗靶点，以减轻缺血性心律失常和相关的心脏功能障碍。