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

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-cGMP independent kinase activation. To explore whether the microvascular effects of nitrite were associated with PKG1α oxidation, we used a C42Ser PKG1α knock-in (KI; "redox-dead") mouse that cannot transduce oxidant signals. Resistance vessels from these 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 PKG1α-KI mice the blood pressure lowering effects 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.

Conclusions: 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.

Translational perspective: despite current pharmacotherapies and interventional procedures, arterial hypertension remains a global health burden. Thus, novel therapeutic interventions are urgently required. Nitrite exerts vasorelaxant effects of potential therapeutic relevance under normal physiological conditions, yet the mechanism(s) remain unknown. Here, we present evidence of how nitrite lowers blood pressure during normoxia via a novel redox mechanism. This occurs independent of nitric oxide by generating hydrogen peroxide and persulfide formation, which subsequently activates the PKG1α by oxidation. Targeting this novel pathway may provide new prospects for anti-hypertensive therapy and other cardiovascular related diseases.

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