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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075265-04
Application #
7433770
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Buxton, Denis B
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$375,931
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kaludercic, Nina; Carpi, Andrea; Nagayama, Takahiro et al. (2014) Monoamine oxidase B prompts mitochondrial and cardiac dysfunction in pressure overloaded hearts. Antioxid Redox Signal 20:267-80
Kaludercic, Nina; Mialet-Perez, Jeanne; Paolocci, Nazareno et al. (2014) Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol 73:34-42
Sivakumaran, Vidhya; Stanley, Brian A; Tocchetti, Carlo G et al. (2013) HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization. Antioxid Redox Signal 19:1185-97
Gao, Wei Dong; Murray, Christopher I; Tian, Ye et al. (2012) Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function. Circ Res 111:1002-11
Kaludercic, Nina; Carpi, Andrea; Menabò, Roberta et al. (2011) Monoamine oxidases (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 1813:1323-32
Tocchetti, Carlo G; Stanley, Brian A; Murray, Christopher I et al. (2011) Playing with cardiac ""redox switches"": the ""HNO way"" to modulate cardiac function. Antioxid Redox Signal 14:1687-98
Ding, Wengang; Li, Zhitao; Shen, Xiaoxu et al. (2011) Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca2+. J Pharmacol Exp Ther 339:825-31
Vecoli, C; Cao, J; Neglia, D et al. (2011) Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice. J Cell Biochem 112:2616-26
Kohr, Mark J; Kaludercic, Nina; Tocchetti, Carlo G et al. (2010) Nitroxyl enhances myocyte Ca2+ transients by exclusively targeting SR Ca2+-cycling. Front Biosci (Elite Ed) 2:614-26
Kaludercic, Nina; Takimoto, Eiki; Nagayama, Takahiro et al. (2010) Monoamine oxidase A-mediated enhanced catabolism of norepinephrine contributes to adverse remodeling and pump failure in hearts with pressure overload. Circ Res 106:193-202

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