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Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1? redox signalling.

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 G1? (PKG1?)].

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 PKG1?, resulting in NO- cyclic guanosine monophosphate (cGMP) independent kinase activation. To explore whether the microvascular effects of nitrite were associated with PKG1? oxidation, we used a Cys42Ser PKG1? knock-in (C42S PKG1? KI; 'redox-dead') mouse that cannot transduce oxidant signals. Resistance vessels from these C42S PKG1? 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 PKG1? 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 PKG1? oxidation/activation. Targeting this novel pathway may provide new prospects for anti-hypertensive therapy.

SUBMITTER: Feelisch M

PROVIDER: S-EPMC6918062 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling.

Feelisch Martin M Akaike Takaaki T Griffiths Kayleigh K Ida Tomoaki T Prysyazhna Oleksandra O Goodwin Joanna J JJ Gollop Nicholas D ND Fernandez Bernadette O BO Minnion Magdalena M Cortese-Krott Miriam M MM Borgognone Alessandra A Hayes Rosie M RM Eaton Philip P Frenneaux Michael P MP Madhani Melanie M

Cardiovascular research 20200101 1

<h4>Aims</h4>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 alterna ...[more]

PMID: 31372656

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