Heart Failure Reviews

, Volume 24, Issue 6, pp 941–948 | Cite as

Advances in research on treatment of heart failure with nitrosyl hydrogen

  • Yanqing Guo
  • Jiyao Xu
  • Li Wu
  • Yongzhi Deng
  • Jingping Wang
  • Jian AnEmail author


Heart failure is the end stage of various heart diseases such as ischemic heart disease, dilated cardiomyopathy, valvular heart disease, congenital heart disease, and hypertensive myocardial damage. It is characterized by a decrease in myocardial contractility, but there is currently no ideal treatment. Nitroxyl hydrogen (HNO) is considered to be a protonated form of NO. It has special chemical properties compared to other nitrogen oxides. In the body of organisms, HNO can participate in all aspects of the occurrence and development of heart failure (HF) and react with some proteins closely related to cardiac activity, changing its spatial structure and exerting cardioprotective effects. In recent years, studies have shown that HNO can inhibit cardiomyocyte hypertrophy, reduce inflammation, enhance myocardial contractility, dilate coronary arteries as well as peripheral blood vessels in early heart failure, and protect the heart against heart failure. This paper, combined with the latest research results at home and abroad, clarifies that nitrosyl hydrogen exerts cardioprotective effects through various processes that occur in the development of heart failure.


Nitrosyl hydrogen Heart failure Sulfhydryl Calcium cycle 



This study was funded by the basic applied research projects in Shanxi Province (grant number 201601D021156) and the Scientific Research Fund of Shanxi Cardiovascular Hospital (grant number 20170203) and the Scientific Research Topics of Shanxi Health commission (grant number 2015070).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not applicable in this study.


  1. 1.
    Fukuto JM, Cisneros CJ, Kinkade RL (2013) A comparison of the chemistry associated with the biological signaling and actions of nitroxyl (HNO) and nitric oxide (NO). J Inorg Biochem 118:201–208. CrossRefPubMedGoogle Scholar
  2. 2.
    Sabbah HN, Tocchetti CG, Wang M, Daya S, Gupta RC, Tunin RS, Mazhari R, Takimoto E, Paolocci N, Cowart D, Colucci WS, Kass DA (2013) Nitroxyl (HNO): a novel approach for the acute treatment of heart failure. Circ Heart Fail 6:1250–1258. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Tocchetti CG, Wang W, Froehlich JP, Huke S, Aon MA, Wilson GM, di Benedetto G, O’Rourke B, Gao WD, Wink DA, Toscano JP, Zaccolo M, Bers DM, Valdivia HH, Cheng H, Kass DA, Paolocci N (2007) Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. Circ Res 100:96–104. CrossRefPubMedGoogle Scholar
  4. 4.
    Chin KY, Michel L, Qin CX, Cao N, Woodman OL, Ritchie RH (2016) The HNO donor Angeli's salt offers potential haemodynamic advantages over NO or dobutamine in ischaemia-reperfusion injury in the rat heart ex vivo. Pharmacol Res 104:165–175. CrossRefPubMedGoogle Scholar
  5. 5.
    Zhu G, Groneberg D, Sikka G, Hori D, Ranek MJ, Nakamura T, Takimoto E, Paolocci N, Berkowitz DE, Friebe A, Kass DA (2015) Soluble guanylate cyclase is required for systemic vasodilation but not positive inotropy induced by nitroxyl in the mouse. Hypertension 65:385–392. CrossRefPubMedGoogle Scholar
  6. 6.
    Dautov RF, Ngo DT, Licari G, Liu S, Sverdlov AL, Ritchie RH et al (2013) The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness. Nitric Oxide 35:72–78. CrossRefPubMedGoogle Scholar
  7. 7.
    Tocchetti CG, Carpi A, Coppola C, Quintavalle C, Rea D, Campesan M, Arcari A, Piscopo G, Cipresso C, Monti MG, de Lorenzo C, Arra C, Condorelli G, di Lisa F, Maurea N (2014) Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction. Eur J Heart Fail 16:358–366. CrossRefPubMedGoogle Scholar
  8. 8.
    Bers DM (2006) Altered cardiac myocyte ca regulation in heart failure. Physiology (Bethesda) 21:380–387. CrossRefGoogle Scholar
  9. 9.
    Curran J, Hinton MJ, Rios E, Bers DM, Shannon TR (2007) Beta-adrenergic enhancement of sarcoplasmic reticulum calcium leak in cardiac myocytes is mediated by calcium/calmodulin-dependent protein kinase. Circ Res 100:391–398. CrossRefPubMedGoogle Scholar
  10. 10.
    Santulli G, Xie W, Reiken SR, Marks AR (2015) Mitochondrial calcium overload is a key determinant in heart failure. Proc Natl Acad Sci U S A 112:11389–11394. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Vafiadaki E, Papalouka V, Arvanitis DA, Kranias EG, Sanoudou D (2009) The role of SERCA2a/PLN complex, ca(2+) homeostasis, and anti-apoptotic proteins in determining cell fate. Pflugers Arch 457:687–700. CrossRefPubMedGoogle Scholar
  12. 12.
    Hasenfuss G, Teerlink JR (2011) Cardiac inotropes: current agents and future directions. Eur Heart J 32:1838–1845. CrossRefPubMedGoogle Scholar
  13. 13.
    Tarone G, Balligand JL, Bauersachs J, Clerk A, De Windt L, Heymans S et al (2014) Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the working group on myocardial function of the European Society of Cardiology. Eur J Heart Fail 16:494–508. CrossRefPubMedGoogle Scholar
  14. 14.
    Nagy L, Pollesello P, Papp Z (2014) Inotropes and inodilators for acute heart failure: sarcomere active drugs in focus. J Cardiovasc Pharmacol 64:199–208. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nediani C, Raimondi L, Borchi E, Cerbai E (2011) Nitric oxide/reactive oxygen species generation and nitroso/redox imbalance in heart failure: from molecular mechanisms to therapeutic implications. Antioxid Redox Signal 14:289–331. CrossRefPubMedGoogle Scholar
  16. 16.
    Irvine JC, Cao N, Gossain S, Alexander AE, Love JE, Qin C, Horowitz JD, Kemp-Harper BK, Ritchie RH (2013) HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO. Am J Physiol Heart Circ Physiol 305:H365–H377. CrossRefPubMedGoogle Scholar
  17. 17.
    Cao N, Wong YG, Rosli S, Kiriazis H, Huynh K, Qin C, du XJ, Kemp-Harper BK, Ritchie RH (2015) Chronic administration of the nitroxyl donor 1-nitrosocyclo hexyl acetate limits left ventricular diastolic dysfunction in a mouse model of diabetes mellitus in vivo. Circ Heart Fail 8:572–581. CrossRefPubMedGoogle Scholar
  18. 18.
    Zgheib C, Kurdi M, Zouein FA, Gunter BW, Stanley BA, Zgheib J, Romero DG, King SB, Paolocci N, Booz GW (2012) Acyloxy nitroso compounds inhibit LIF signaling in endothelial cells and cardiac myocytes: evidence that STAT3 signaling is redox-sensitive. PLoS One 7:e43313. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Lin EQ, Irvine JC, Cao AH, Alexander AE, Love JE, Patel R, McMullen JR, Kaye DM, Kemp-Harper BK, Ritchie RH (2012) Nitroxyl (HNO) stimulates soluble guanylyl cyclase to suppress cardiomyocyte hypertrophy and superoxide generation. PLoS One 7:e34892. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chin KY, Qin C, Cao N, Kemp-Harper BK, Woodman OL, Ritchie RH (2014) The concomitant coronary vasodilator and positive inotropic actions of the nitroxyl donor Angeli's salt in the intact rat heart: contribution of soluble guanylyl cyclase-dependent and -independent mechanisms. Br J Pharmacol 171:1722–1734. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fukuto JM, Jackson MI, Kaludercic N, Paolocci N (2008) Examining nitroxyl in biological systems. Methods Enzymol 440:411–431. CrossRefPubMedGoogle Scholar
  22. 22.
    Alexander SP, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M et al (2013) The concise guide to PHARMACOLOGY 2013/14: enzymes. Br J Pharmacol 170:1797–1867. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Keceli G, Moore CD, Labonte JW, Toscano JP (2013) NMR detection and study of hydrolysis of HNO-derived sulfinamides. Biochemistry 52:7387–7396. CrossRefPubMedGoogle Scholar
  24. 24.
    Kumar MR, Fukuto JM, Miranda KM, Farmer PJ (2010) Reactions of HNO with heme proteins: new routes to HNO-heme complexes and insight into physiological effects. Inorg Chem 49:6283–6292. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nagahara N (2011) Intermolecular disulfide bond to modulate protein function as a redox-sensing switch. Amino Acids 41:59–72. CrossRefPubMedGoogle Scholar
  26. 26.
    Fukuto JM, Carrington SJ (2011) HNO signaling mechanisms. Antioxid Redox Signal 14:1649–1657. CrossRefPubMedGoogle Scholar
  27. 27.
    Tocchetti CG, Stanley BA, Murray CI, Sivakumaran V, Donzelli S, Mancardi D, Pagliaro P, Gao WD, van Eyk J, Kass DA, Wink DA, Paolocci N (2011) Playing with cardiac “redox switches”: the “HNO way” to modulate cardiac function. Antioxid Redox Signal 14:1687–1698. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Meissner G (2010) Regulation of ryanodine receptor ion channels through posttranslational modifications. Curr Top Membr 66:91–113. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ge Y, Moss RL (2012) Nitroxyl, redox switches, cardiac myofilaments, and heart failure: a prequel to novel therapeutics? Circ Res 111:954–956. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sivakumaran V, Stanley BA, Tocchetti CG, Ballin JD, Caceres V, Zhou L, Keceli G, Rainer PP, Lee DI, Huke S, Ziolo MT, Kranias EG, Toscano JP, Wilson GM, O'Rourke B, Kass DA, Mahaney JE, Paolocci N (2013) HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization. Antioxid Redox Signal 19:1185–1197. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lopez BE, Rodriguez CE, Pribadi M, Cook NM, Shinyashiki M, Fukuto JM (2005) Inhibition of yeast glycolysis by nitroxyl (HNO): mechanism of HNO toxicity and implications to HNO biology. Arch Biochem Biophys 442:140–148. CrossRefPubMedGoogle Scholar
  32. 32.
    Cheong E, Tumbev V, Abramson J, Salama G, Stoyanovsky DA (2005) Nitroxyl triggers Ca2+ release from skeletal and cardiac sarcoplasmic reticulum by oxidizing ryanodine receptors. Cell Calcium 37:87–96. CrossRefPubMedGoogle Scholar
  33. 33.
    Adak S, Wang Q, Stuehr DJ (2000) Arginine conversion to nitroxide by tetrahydrobiopterin-free neuronal nitric-oxide synthase. Implications for mechanism. J Biol Chem 275:33554–33561. CrossRefGoogle Scholar
  34. 34.
    DuMond JF, King SB (2011) The chemistry of nitroxyl-releasing compounds. Antioxid Redox Signal 14:1637–1648. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Miranda KM, Dutton AS, Ridnour LA, Foreman CA, Ford E, Paolocci N, Katori T, Tocchetti CG, Mancardi D, Thomas DD, Espey MG, Houk KN, Fukuto JM, Wink DA (2005) Mechanism of aerobic decomposition of Angeli’s salt (sodium trioxodinitrate) at physiological pH. J Am Chem Soc 127:722–731. CrossRefPubMedGoogle Scholar
  36. 36.
    Miranda KM, Katori T, Torres de Holding CL, Thomas L, Ridnour LA, McLendon WJ et al (2005) Comparison of the NO and HNO donating properties of diazeniumdiolates: primary amine adducts release HNO in vivo. J Med Chem 48:8220–8228. CrossRefPubMedGoogle Scholar
  37. 37.
    Gao WD, Murray CI, Tian Y, Zhong X, DuMond JF, Shen X et al (2012) Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function. Circ Res 111:1002–1011. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ritchie RH, Rosenkranz AC, Huynh LP, Stephenson T, Kaye DM, Dusting GJ (2004) Activation of IP prostanoid receptors prevents cardiomyocyte hypertrophy via cAMP-dependent signaling. Am J Physiol Heart Circ Physiol 287:H1179–H1185. CrossRefPubMedGoogle Scholar
  39. 39.
    Selvetella G, Hirsch E, Notte A, Tarone G, Lembo G (2004) Adaptive and maladaptive hypertrophic pathways: points of convergence and divergence. Cardiovasc Res 63:373–380. CrossRefPubMedGoogle Scholar
  40. 40.
    Ritchie RH, Irvine JC, Rosenkranz AC, Patel R, Wendt IR, Horowitz JD, Kemp-Harper BK (2009) Exploiting cGMP-based therapies for the prevention of left ventricular hypertrophy: NO* and beyond. Pharmacol Ther 124:279–300. CrossRefPubMedGoogle Scholar
  41. 41.
    Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128:191–227. CrossRefPubMedGoogle Scholar
  42. 42.
    Xu Q, Dalic A, Fang L, Kiriazis H, Ritchie RH, Sim K, Gao XM, Drummond G, Sarwar M, Zhang YY, Dart AM, du XJ (2011) Myocardial oxidative stress contributes to transgenic beta(2)-adrenoceptor activation-induced cardiomyopathy and heart failure. Br J Pharmacol 162:1012–1028. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Purcell NH, Wilkins BJ, York A, Saba-El-Leil MK, Meloche S, Robbins J et al (2007) Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci U S A 104:14074–14079. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bermejo E, Saenz DA, Alberto F, Rosenstein RE, Bari SE, Lazzari MA (2005) Effect of nitroxyl on human platelets function. Thromb Haemost 94:578–584. CrossRefPubMedGoogle Scholar
  45. 45.
    Taflin C, Favier B, Baudhuin J, Savenay A, Hemon P, Bensussan A, Charron D, Glotz D, Mooney N (2011) Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions. Proc Natl Acad Sci U S A 108:2891–2896. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Hertelendi Z, Toth A, Borbely A, Galajda Z, van der Velden J, Stienen GJ et al (2008) Oxidation of myofilament protein sulfhydryl groups reduces the contractile force and its Ca2+ sensitivity in human cardiomyocytes. Antioxid Redox Signal 10:1175–1184. CrossRefPubMedGoogle Scholar
  47. 47.
    Lancel S, Zhang J, Evangelista A, Trucillo MP, Tong X, Siwik DA, Cohen RA, Colucci WS (2009) Nitroxyl activates SERCA in cardiac myocytes via glutathiolation of cysteine 674. Circ Res 104:720–723. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS et al (2002) Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. Jama 287:1541–1547CrossRefGoogle Scholar
  49. 49.
    Froehlich JP, Mahaney JE, Keceli G, Pavlos CM, Goldstein R, Redwood AJ, Sumbilla C, Lee DI, Tocchetti CG, Kass DA, Paolocci N, Toscano JP (2008) Phospholamban thiols play a central role in activation of the cardiac muscle sarcoplasmic reticulum calcium pump by nitroxyl. Biochemistry 47:13150–13152. CrossRefPubMedGoogle Scholar
  50. 50.
    Dai T, Tian Y, Tocchetti CG, Katori T, Murphy AM, Kass DA, Paolocci N, Gao WD (2007) Nitroxyl increases force development in rat cardiac muscle. J Physiol 580:951–960. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Katori T, Hoover DB, Ardell JL, Helm RH, Belardi DF, Tocchetti CG, Forfia PR, Kass DA, Paolocci N (2005) Calcitonin gene-related peptide in vivo positive inotropy is attributable to regional sympatho-stimulation and is blunted in congestive heart failure. Circ Res 96:234–243. CrossRefPubMedGoogle Scholar
  52. 52.
    Andrews KL, Lumsden NG, Farry J, Jefferis AM, Kemp-Harper BK, Chin-Dusting JP (2015) Nitroxyl: a vasodilator of human vessels that is not susceptible to tolerance. Clin Sci (Lond) 129:179–187. CrossRefGoogle Scholar
  53. 53.
    Irvine JC, Ritchie RH, Favaloro JL, Andrews KL, Widdop RE, Kemp-Harper BK (2008) Nitroxyl (HNO): the Cinderella of the nitric oxide story. Trends Pharmacol Sci 29:601–608. CrossRefPubMedGoogle Scholar
  54. 54.
    Zeller A, Wenzl MV, Beretta M, Stessel H, Russwurm M, Koesling D, Schmidt K, Mayer B (2009) Mechanisms underlying activation of soluble guanylate cyclase by the nitroxyl donor Angeli’s salt. Mol Pharmacol 76:1115–1122. CrossRefPubMedGoogle Scholar
  55. 55.
    Favaloro JL, Kemp-Harper BK (2009) Redox variants of NO (NO {middle dot} and HNO) elicit vasorelaxation of resistance arteries via distinct mechanisms. Am J Physiol Heart Circ Physiol 296:H1274–H1280. CrossRefPubMedGoogle Scholar
  56. 56.
    Favaloro JL, Kemp-Harper BK (2007) The nitroxyl anion (HNO) is a potent dilator of rat coronary vasculature. Cardiovasc Res 73:587–596. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of CardiologyShanxi Cardiovascular HospitalTaiyuanChina

Personalised recommendations