Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides and oxidation of protein kinase G 1α redox signaling

Research output: Contribution to journalArticlepeer-review

Authors

  • Martin Feelisch
  • Takaaki Akaike
  • Tomoaki Ida
  • Oleksandra Prysyahna
  • Joanna J Goodwin
  • Nicholas D Gollop
  • Bernadette O Fernandez
  • Magdalena Minnion
  • Miriam M Cortese-Krott
  • Rosie M Hayes
  • Philip Eaton
  • Michael P Frenneaux

Colleges, School and Institutes

External organisations

  • Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton
  • Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • Department of Cardiology, Cardiovascular Division, King's College of London, London, UK.
  • Division of Cardiology, Heinrich Heine University, Düsseldorf, Germany.
  • Norwich Medical School, University of East Anglia, Norwich, UK.
  • Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Abstract

AIMS: Under hypoxic conditions, nitrite (NO2-) can be reduced to nitric oxide (NO) eliciting vasorelaxation. However, nitrite also exerts vasorelaxant effects of potential therapeutic relevance under normal physiological conditions via undetermined mechanisms. We, therefore, sought to investigate the mechanism(s) by which nitrite regulates the vascular system in normoxia and, specifically, whether the biological effects are a result of NO generation (as in hypoxia) or mediated via alternative mechanisms involving classical downstream targets of NO [e.g. effects on protein kinase G1α (PKG1α)]. METHODS AND RESULTS: Ex vivo myography revealed that, unlike in thoracic aorta (conduit vessels), the vasorelaxant effects of nitrite in mesenteric resistance vessels from wild-type (WT) mice were NO-independent. Oxidants such as H2O2 promote disulfide formation of PKG1α, resulting in NO- cyclic guanosine monophosphate (cGMP) independent kinase activation. To explore whether the microvascular effects of nitrite were associated with PKG1α oxidation, we used a Cys42Ser PKG1α knock-in (C42S PKG1α KI; 'redox-dead') mouse that cannot transduce oxidant signals. Resistance vessels from these C42S PKG1α KI mice were markedly less responsive to nitrite-induced vasodilation. Intraperitoneal (i.p.) bolus application of nitrite in conscious WT mice induced a rapid yet transient increase in plasma nitrite and cGMP concentrations followed by prolonged hypotensive effects, as assessed using in vivo telemetry. In the C42S PKG1α KI mice, the blood pressure lowering effects of nitrite were lower compared to WT. Increased H2O2 concentrations were detected in WT resistance vessel tissue challenged with nitrite. Consistent with this, increased cysteine and glutathione persulfide levels were detected in these vessels by mass spectrometry, matching the temporal profile of nitrite's effects on H2O2 and blood pressure. CONCLUSION: Under physiological conditions, nitrite induces a delayed and long-lasting blood pressure lowering effect, which is NO-independent and occurs via a new redox mechanism involving H2O2, persulfides, and PKG1α oxidation/activation. Targeting this novel pathway may provide new prospects for anti-hypertensive therapy.

Bibliographic note

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Details

Original languageEnglish
Article numbercvz202
Pages (from-to)51-62
Number of pages12
JournalCardiovascular Research
Volume116
Issue number1
Early online date31 Jul 2019
Publication statusPublished - 1 Jan 2020

Keywords

  • Blood pressure, Hydrogen peroxide, Nitrite, Persulfides, Redox