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; Akaike, Takaaki; Griffiths, Kayleigh; Ida, Tomoaki; Prysyazhna, Oleksandra; Goodwin, Joanna Jane; Gollop, Nicholas D.; Fernandez, Bernadette; Minnion, Magdalena; Cortese‐Krott, Miriam M.; Borgognone, Alessandra; Hayes, Rosie M; Eaton, Philip; Frenneaux, Michael; Madhani, Melanie

doi:10.1093/cvr/cvz202

Cited by 38 publications

(22 citation statements)

References 37 publications

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“…In fact, this response was also found with nitrate administration and significantly attenuated by the use of oral mouthwash, which impaired the enterosalivary cycle of nitrate and prevented nitrate from being reduced to nitrite, thus reducing the increases in circulating S-nitrosothiols and vascular protein nitrosylation [ 3 , 10 , 11 ]. Several recent studies by other groups have described vascular effects of nitrite that are not necessarily associated with increased NO production [ [27] , [28] , [29] ], thus strongly suggesting the involvement of other pathways such as catalase inhibition [ 28 ] or increased S-nitrosylation 26 as possible mechanisms activated by nitrite.…”

Section: Discussionmentioning

confidence: 99%

Oral nitrite treatment increases S-nitrosylation of vascular protein kinase C and attenuates the responses to angiotensin II

et al. 2021

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Nitrate and nitrite supplement deficient endogenous nitric oxide (NO) formation. While these anions may generate NO, recent studies have shown that circulating nitrite levels do not necessarily correlate with the antihypertensive effect of oral nitrite administration and that formation of nitrosylated species (RXNO) in the stomach is critically involved in this effect. This study examined the possibility that RXNO formed in the stomach after oral nitrite administration promotes target protein nitrosylation in the vasculature, inhibits vasoconstriction and the hypertensive responses to angiotensin II. Our results show that oral nitrite treatment enhances circulating RXNO concentrations (measured by ozone-based chemiluminescence methods), increases aortic protein kinase C (PKC) nitrosylation (measured by resin-assisted capture SNO-RAC method), and reduces both angiotensin II-induced vasoconstriction (isolated aortic ring preparation) and hypertensive ( in vivo invasive blood pressure measurements) effects implicating PKC nitrosylation as a key mechanism for the responses to oral nitrite. Treatment of rats with the nitrosylating compound S-nitrosoglutathione (GSNO) resulted in the same effects described for oral nitrite. Moreover, partial depletion of thiols with buthionine sulfoximine prevented PKC nitrosylation and the blood pressure effects of oral nitrite. Further confirming a role for PKC nitrosylation, preincubation of aortas with GSNO attenuated the responses to both angiotensin II and to a direct PKC activator, and this effect was attenuated by ascorbate (reverses GSNO-induced nitrosylation). GSNO-induced nitrosylation also inhibited the increases in Ca2+ mobilization in angiotensin II-stimulated HEK293T cells expressing angiotensin type 1 receptor. Together, these results are consistent with the idea that PKC nitrosylation in the vasculature may underlie oral nitrite treatment-induced reduction in the vascular and hypertensive responses to angiotensin II.

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Section: Discussionmentioning

confidence: 99%

Oral nitrite treatment increases S-nitrosylation of vascular protein kinase C and attenuates the responses to angiotensin II

et al. 2021

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“…In the endothelium, H 2 O 2 acts as a vasodilator and has been considered to be an endotheliumderived relaxing factor, effects that are induced largely through activation of PKG1a and posttranslational modifications involving S-glutathionylation. 47,48 Increased intracellular H 2 O 2 promotes phosphorylation of p66Shc, a key mitochondrial ROS regulator that involves vascular endothelial growth factor, which is important in endothelial cell migration, proliferation, and angiogenesis. 49 In vascular smooth muscle cells, we demonstrated that H 2 O 2 induces posttranslational modification of ERK1/2 and p38MAPK through tyrosine kinaseedependent, protein kinase C (PKC)eindependent mechanisms, processes that are up-regulated in hypertension.…”

Section: R Esum Ementioning

confidence: 99%

Oxidative Stress: A Unifying Paradigm in Hypertension

Touyz

Ríos

Alves-Lopes

et al. 2020

Canadian Journal of Cardiology

187

129

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The etiology of hypertension involves complex interactions among genetic, environmental, and pathophysiologic factors that influence many regulatory systems. Hypertension is characteristically associated with vascular dysfunction, cardiovascular remodelling, renal dysfunction, and stimulation of the sympathetic nervous system. Emerging evidence indicates that the immune system is also important and that activated immune cells migrate and accumulate in tissues promoting inflammation, fibrosis, and target-organ damage. Common to these processes is oxidative stress, defined as an imbalance between

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“…2012; Feelisch et al . 2019). To our knowledge, the metabolic fate of NO and NOx has not been studied in the placenta.…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide metabolism in the human placenta during aberrant maternal inflammation

Mukosera

Clark

Ngo

et al. 2020

The Journal of Physiology

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Key points Nitric oxide (NO) is a gasotransmitter with important physiological and pathophysiological roles in pregnancy. There is limited information available about the sources and metabolism of NO and its bioactive metabolites (NOx) in both normal and complicated pregnancies. The present study characterized and quantified endogenous NOx in human and mouse placenta following determination of the stability of exogenous NOx in placental homogenates. NOx have differential stability in placental homogenates. NO and iron nitrosyl species (FeNOs), are relatively unstable in placental homogenates from normal placentas. Exogenous NO, nitrite and nitrosothiols react with placental homogenates to form iron nitrosyl complexes. FeNOs were also detected endogenously in mouse and human placenta. NOx levels in placental villous tissue are increased in fetal growth restriction vs. placentas from women with normal pregnancies, particularly in fetal growth restriction associated with pre‐eclampsia. Villitis was not associated, however, with an increase in NOx levels in either normotensive or pre‐eclamptic placentas. The results call for further investigation of FeNOs in normal and complicated pregnancies. Abstract Nitric oxide (NO) is a gasotransmitter with important roles in pregnancy under both physiological and pathophysiological conditions. Although products of NO metabolism (NOx) also have significant bioactivity, little is known about the role of NO and NOx under conditions of aberrant placental inflammation during pregnancy. An ozone‐based chemiluminescence approach was used to investigate the stability and metabolic fate of NOx in human placental homogenates from uncomplicated pregnancies in healthy mothers compared to that in placental tissue from normotensive and pre‐eclamptic pregnancies complicated with fetal growth restriction (FGR) with and without villitis of unknown aetiology. We hypothesized that placental NOx would be increased in FGR vs. normal tissue, and be further increased in villitis vs. non‐villitis placentas. Findings indicate that nitrate, nitrite and nitrosothiols, but not NO or iron nitrosyl species (FeNOs), are relatively stable in placental homogenates from normal placentas, and that NO, nitrite and nitrosothiols react with placental homogenates to form iron nitrosyl complexes. Furthermore, NOx levels in placental villous tissue are increased in FGR vs. placentas from women with normal pregnancies, particularly in FGR associated with pre‐eclampsia. However, in contrast to our hypothesis, villitis was not associated with an increase in NOx levels in either normotensive or pre‐eclamptic placentas. Our results also strongly support the involvement of FeNOs in both mouse and human placenta, and call for their further study as a critical mechanistic link between pre‐eclampsia and fetal growth restriction.

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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

Cited by 38 publications

References 37 publications

Oral nitrite treatment increases S-nitrosylation of vascular protein kinase C and attenuates the responses to angiotensin II

Oral nitrite treatment increases S-nitrosylation of vascular protein kinase C and attenuates the responses to angiotensin II

Oxidative Stress: A Unifying Paradigm in Hypertension

Nitric oxide metabolism in the human placenta during aberrant maternal inflammation

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