Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling

Carlo G. Tocchetti, Wang Wang, Jeffrey P. Froehlich, Sabine Huke, Miguel A. Aon, Gerald M. Wilson, Giulietta Di Benedetto, Brian O'Rourke, Wei Dong Gao, David A. Wink, John P. Toscano, Manuela Zaccolo, Donald M Bers, Hector H. Valdivia, Heping Cheng, David A. Kass, Nazareno Paolocci

Research output: Contribution to journalArticle

167 Scopus citations

Abstract

Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca. A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca pump and the ryanodine receptor 2, leading to increased Ca uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca-release channels and accelerates Ca reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure.

Original languageEnglish (US)
Pages (from-to)96-104
Number of pages9
JournalCirculation Research
Volume100
Issue number1
DOIs
StatePublished - Jan 2007
Externally publishedYes

Keywords

  • Contractility
  • Excitation/contraction coupling
  • Nitroxyl
  • Ryanodine receptor
  • Sarcoplasmic reticulum Ca -ATPase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Tocchetti, C. G., Wang, W., Froehlich, J. P., Huke, S., Aon, M. A., Wilson, G. M., Di Benedetto, G., O'Rourke, B., Gao, W. D., Wink, D. A., Toscano, J. P., Zaccolo, M., Bers, D. M., Valdivia, H. H., Cheng, H., Kass, D. A., & Paolocci, N. (2007). Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. Circulation Research, 100(1), 96-104. https://doi.org/10.1161/01.RES.0000253904.53601.c9