Nitroxyl cardiac effects are mediated by cAMP/PKA signal

硝酰心脏效应由 cAMP/PKA 信号介导

• 批准号: 7255482
• 负责人: Nazareno Paolocci
• 金额: $ 37.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7255482
• 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

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来治疗急性失代偿，但这种相互作用可能是拮抗的。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舒张心脏作用。有趣的是，与 NO 供体和硝酸盐相反，这些心脏效应是 β 刺激的附加作用，基本上不受 β 阻断的影响，并且在正常和衰竭的心脏中类似。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，但最新数据表明这不是唯一的机制，并且会发生直接、有效的肌细胞作用。该提议的指导性假设是 HNO/NO- 供体直接并显着增强心肌细胞的收缩性，与 NO 不同，这与 cAMP 和 PKA 激活的升高有关，并且在正常和衰竭心脏的心肌细胞中具有类似的活性。研究将检验这一假设，确定 HNO NO- 影响兴奋-收缩耦合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。澄清 HNO/NO- 的作用机制将极大地促进我们对该药物作为潜在的新型心力衰竭疗法的理解和潜在用途。这三个目标是测试 HNO/NO- 是否以及如何影响兴奋-收缩耦合、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，并采用药理学和基因工程方法来剖析关键途径。这些研究将为阐明新型硝酰基/cAMP/PKA范例及其发展为心力衰竭疗法的潜力提供关键的基础工作。