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Nitroxyl cardiac effects are mediated by cAMP/PKA signal

硝酰心脏效应由 cAMP/PKA 信号介导

基本信息

批准号：
7433770
负责人：
Nazareno Paolocci
金额：
$ 37.59万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2005-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7433770
关键词：
Acute Adenylate Cyclase Adrenergic Agents Adrenergic Receptor Agonist Anions Blood Vessels Ca(2+)-Transporting ATPase Calcitonin Gene-Related Peptide Calcium Cardiac Cardiac Myocytes Cholinergic Fibers Coupled Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Data Electrons Elevation Engineering Failure Fluorescence Resonance Energy Transfer Frequencies Genetic Engineering Heart Heart failure Holoenzymes Individual Link Measures Mediating Membrane Methods Modeling Morbidity - disease rate Mus Muscle Cells Neonatal Nitrates Nitric Oxide Nitric Oxide Donors Normal Cell Oxidation-Reduction Pathway interactions Phosphorylation Production Protein Overexpression Proteins Receptor Signaling Relaxation Reporting Research Personnel Role SERCA2a Sarcoplasmic Reticulum Signal Transduction Societies Surface Techniques Testing Transgenic Mice Vasodilation Vasodilator Agents Work adrenergic aged base improved in vivo inhibitor/antagonist mortality nitrate nitroxyl novel prevent receptor response

项目摘要

DESCRIPTION (provided by applicant): Cardiac failure is the leading cause of morbidity and mortality among aged individuals in Westernized societies. While acute decompensation is treated with combined vascular unloading via nitrates and beta-adrenergic stimulation, this interaction can be antagonistic. We recently discovered that nitroxyl anion (HNO/NO-), the one-electron reduced form of NO, induces marked vasodilation and marked positive inotropic and lusitropic cardiac effects. Intriguingly, and opposite to NO donors and nitrates, these cardiac effects are additive to beta-stimulation, largely unaffected by beta-blockade, and similar in normal and failing hearts. While initial in vivo studies suggested a role of calcitonin gene-related peptide (CGRP) release, newer data indicates this is not the sole mechanism, and that direct, potent myocyte action occurs. The guiding hypothesis of this proposal is that HNO/NO- donors directly and substantially enhance myocyte contractility, that unlike NO, this is linked to elevation of cAMP and PKA activation, and is similarly active in myocytes from normal and failing hearts. Studies will test this hypothesis, determine basic mechanisms by which HNO NO- effects excitation-contraction coupling and redox modulation, directly test a link to cAMP and PKA, and define interactions of HNO/NO- with adrenergic receptor signaling. Clarification of the mechanism of action of HNO/NO- will greatly advance our understanding and potential use of this agent as a potential and novel heart failure therapy. The three aims are to test whether and how HNO/NO- influences excitation-contraction coupling, directly test the link to cAMP and PKA, define redox modulation, and interactions of HNO/NO- with adrenergic receptor signaling. Studies are largely conducted in isolated myocytes, employing fluorescent methods to define cAMP signaling and localization, and pharmacologic and genetic engineering approaches to dissect key pathways. These studies will provide key ground work clarifying a novel nitroxyl/cAMP/PKA paradigm, and its potential to develop into a therapy for cardiac failure.

描述（由申请人提供）：心力衰竭是西方社会中老年人发病和死亡的主要原因。虽然通过硝酸盐和β-肾上腺素能刺激联合血管卸载治疗急性失代偿，但这种相互作用可能是拮抗性的。我们最近发现，硝酰基阴离子（HNO/NO-）（NO的单电子还原形式）可诱导显着的血管舒张以及显着的正性肌力和抗心律失常心脏作用。有趣的是，与NO供体和硝酸盐相反，这些心脏效应是β刺激的叠加效应，基本上不受β阻断的影响，并且在正常和衰竭的心脏中相似。虽然最初的体内研究表明降钙素基因相关肽（CGRP）释放的作用，但新的数据表明这不是唯一的机制，而是直接的，有效的肌细胞作用。该建议的指导假设是HNO/NO-供体直接且显著地增强肌细胞收缩性，与NO不同，这与cAMP和PKA活化的升高有关，并且在来自正常和衰竭心脏的肌细胞中具有类似的活性。研究将测试这一假设，确定HNO NO-影响兴奋-收缩偶联和氧化还原调节的基本机制，直接测试与cAMP和PKA的联系，并定义HNO/NO-与肾上腺素能受体信号传导的相互作用。阐明HNO/NO-的作用机制将极大地促进我们对这种药物作为潜在的新型心力衰竭治疗方法的理解和潜在用途。这三个目的是测试HNO/NO-是否以及如何影响兴奋-收缩偶联，直接测试与cAMP和PKA的联系，定义氧化还原调节，以及HNO/NO-与肾上腺素能受体信号传导的相互作用。研究主要在分离的肌细胞中进行，采用荧光方法来定义cAMP信号传导和定位，以及药理学和基因工程方法来剖析关键途径。这些研究将为阐明一种新的硝酰基/cAMP/PKA范式及其发展成为心力衰竭治疗方法的潜力提供关键的基础工作。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Monoamine oxidases as sources of oxidants in the heart.

DOI：
10.1016/j.yjmcc.2013.12.032
发表时间：
2014-08
期刊：
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
影响因子：
5
作者：
Kaludercic, Nina;Mialet-Perez, Jeanne;Paolocci, Nazareno;Parini, Angelo;Di Lisa, Fabio
通讯作者：
Di Lisa, Fabio

Mother was right: eat your vegetables and do not spit! When oral nitrate helps with high blood pressure.

妈妈说得对：吃蔬菜，别吐口水！