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: 7101684
• 负责人: Nazareno Paolocci
• 金额: $ 37.8万
• 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/7101684
• 关键词: adrenergic receptor; biological signal transduction; calcitonin gene related peptide; cardiac myocytes; cyclic AMP; enzyme activity; heart contraction; heart failure; laboratory mouse; nitrogen oxides; protein kinase A; vasodilation

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）：心力衰竭是西方化社会中老年人发病和死亡的主要原因。虽然急性失代偿可以通过硝酸盐和β -肾上腺素能刺激联合血管卸载来治疗，但这种相互作用可能是拮抗的。我们最近发现硝基阴离子（HNO/NO-），一氧化氮的单电子还原形式，诱导显著的血管舒张和显著的正性肌力和滑脱性心脏作用。有趣的是，与NO供体和硝酸盐相反，这些对心脏的影响是与β刺激相结合的，在很大程度上不受β阻断的影响，在正常和衰竭的心脏中也是类似的。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，但较新的数据表明这不是唯一的机制，直接的，有效的肌细胞作用发生。该建议的指导假设是，HNO/NO-供体直接和实质性地增强了心肌细胞的收缩性，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同样活跃。研究将验证这一假设，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，并确定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HNO/NO-作为一种潜在的新型心力衰竭治疗药物的认识和应用。三个目的是测试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，采用荧光方法定义cAMP信号和定位，并采用药理学和基因工程方法解剖关键通路。这些研究将为阐明一种新的硝基/cAMP/PKA模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。