The role of eNOS on the compensatory regulation of vascular tonus by H2S in mouse carotid arteries

Ertuna, Elif; Loot, Annemarieke E.; Fleming, Ingrid; Yetik‐Anacak, Gunay

doi:10.1016/j.niox.2017.04.007

Cited by 8 publications

(5 citation statements)

References 44 publications

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“…Additional data in the present study show that the expression of CTH, the formation of H 2 S and the dilator response to the H 2 S donor NaHS are all increased in arteries isolated from chicken embryos chronically treated with NAC during normoxic conditions, relative to untreated normoxic incubation, and the outcomes were elevated even further in NAC‐chronically treated hypoxic chicken embryos. Notably, data from eNOS knockout and transgenic mice show that H 2 S‐ and eNOS‐mediated vasorelaxant actions are reciprocally regulated, with enhanced H 2 S dilator effects under conditions of impaired NO synthesis (Ertuna et al., 2017). Therefore, the data in the present study show that chronic treatment with NAC enhances the synthesis and vasodilator function of H 2 S in normoxic chicken embryos and that these effects can be sensitized in hypoxic chicken embryos.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation by hypoxia, N‐acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos

Krause,

Paz,

Garrud

et al. 2024

The Journal of Physiology

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Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N‐acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth‐restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near‐term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ‐lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third‐order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third‐to‐fourth order chorionic arteries from FGR pregnancies and in third‐order femoral arteries from hypoxic chicken embryos. This NAC‐induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. imageKey points Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N‐acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.

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Section: Discussionmentioning

confidence: 99%

Epigenetic regulation by hypoxia, N‐acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos

Krause,

Paz,

Garrud

et al. 2024

The Journal of Physiology

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“…Not only H 2 S regulates NO production/activity, NO also influences H 2 S-induced response. eNOS −/− mice exhibited significantly enhanced relaxation to L-cysteine in carotid arteries whereas overexpression of eNOS suppressed L-cysteine-induced relaxation, which suggested that endogenously produced H 2 S can compensate for impaired vasodilatory responses when NO is deficient while eNOS/NO abundance limits endogenous H 2 S-induced vascular responses [50]. The cross-talk between H 2 S and NO in different grades of hyperhomocysteinemia is worthy of study, which will help us gain a comprehensive understanding of the role of these two important gasotransmitters in vascular pathology associated with hyperhomocysteinemia.…”

Section: H2s Antagonizes Homocysteine-induced Vascular Injury: Rolmentioning

confidence: 99%

Imbalance of Homocysteine and H₂S: Significance, Mechanisms, and Therapeutic Promise in Vascular Injury

Yang

2019

Oxidative Medicine and Cellular Longevity

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While the role of hyperhomocysteinemia in cardiovascular pathogenesis continuously draws attention, deficiency of hydrogen sulfide (H2S) has been growingly implicated in cardiovascular diseases. Generation of H2S is closely associated with the metabolism of homocysteine via key enzymes such as cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). The level of homocysteine and H2S is regulated by each other. Metabolic switch in the activity of CBS and CSE may occur with a resultant operating preference change of these enzymes in homocysteine and H2S metabolism. This paper presented an overview regarding (1) linkage between the metabolism of homocysteine and H2S, (2) mutual regulation of homocysteine and H2S, (3) imbalance of homocysteine and H2S in cardiovascular disorders, (4) mechanisms underlying the protective effect of H2S against homocysteine-induced vascular injury, and (5) the current status of homocysteine-lowering and H2S-based therapies for cardiovascular disease. The metabolic imbalance of homocysteine and H2S renders H2S/homocysteine ratio a potentially reliable biomarker for cardiovascular disease and development of drugs or interventions targeting the interplay between homocysteine and H2S to maintain the endogenous balance of these two molecules may hold an even bigger promise for management of vascular disorders than targeting homocysteine or H2S alone.

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“…Therefore, it is likely that different mechanisms and effects may occur when an endogenous source, such as the CBS substrate, L‐cysteine, is used. For example, in carotid arteries from eNOS −/− mice, relaxation to NaHS, an H 2 S donor, is reduced, but relaxation to L‐cysteine is increased (Ertuna, Loot, Fleming, & Yetik‐Anacak, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…For example, in carotid arteries from eNOS −/− mice, relaxation to NaHS, an H 2 S donor, is reduced, but relaxation to L-cysteine is increased (Ertuna, Loot, Fleming, & Yetik-Anacak, 2017).…”

mentioning

confidence: 99%

L‐cysteine/cystathionine‐β‐synthase‐induced relaxation in mouse aorta involves a L‐serine/sphingosine‐1‐phosphate/NO pathway

Mitidieri

Gurgone

Caiazzo

et al. 2019

British J Pharmacology

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Background and Purpose Among the three enzymes involved in the transsulfuration pathway, only cystathionine β‐synthase (CBS) converts L‐cysteine into L‐serine and H2S. L‐serine is also involved in the de novo sphingolipid biosynthesis through a condensation with palmitoyl‐CoA by the action of serine palmitoyltransferase (SPT). Here, we have investigated if L‐serine contributes to the vasorelaxant effect. Experimental Approach The presence of CBS in mouse vascular endothelium was assessed by immunohistochemistry and immunofluorescence. The relaxant activity of L‐serine (0.1–300 μM) and L‐cysteine (0.1–300 μM) was estimated on mouse aorta rings, with or without endothelium. A pharmacological modulation study evaluated NO and sphingosine‐1‐phosphate (S1P) involvement. Levels of NO and S1P were also measured following incubation of aorta tissue with either L‐serine (1, 10, and 100 μM) or L‐cysteine (10, 100 μM, and 1 mM). Key Results L‐serine relaxed aorta rings in an endothelium‐dependent manner. The vascular effect was reduced by L‐NG‐nitro‐arginine methyl ester and wortmaninn. A similar pattern was obtained with L‐cysteine. The S1P1 receptor antagonist (W146) or the SPT inhibitor (myriocin) reduced either L‐serine or L‐cysteine relaxant effect. L‐serine or L‐cysteine incubation increased NO and S1P levels in mouse aorta. Conclusions and Implications L‐serine, a by‐product formed within the transsulfuration pathway starting from L‐cysteine via CBS, contributes to the vasodilator action of L‐cysteine. The L‐serine effect involves both NO and S1P. This mechanism could be involved in the marked dysregulation of vascular tone in hyperhomocysteinemic patients (CBS deficiency) and may represent a feasible therapeutic target. Linked Articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

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The role of eNOS on the compensatory regulation of vascular tonus by H2S in mouse carotid arteries

Cited by 8 publications

References 44 publications

Epigenetic regulation by hypoxia, N‐acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos

Epigenetic regulation by hypoxia, N‐acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos

Imbalance of Homocysteine and H₂S: Significance, Mechanisms, and Therapeutic Promise in Vascular Injury

L‐cysteine/cystathionine‐β‐synthase‐induced relaxation in mouse aorta involves a L‐serine/sphingosine‐1‐phosphate/NO pathway

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The role of eNOS on the compensatory regulation of vascular tonus by H2S in mouse carotid arteries

Cited by 8 publications

References 44 publications

Epigenetic regulation by hypoxia, N‐acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos

Epigenetic regulation by hypoxia, N‐acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos

Imbalance of Homocysteine and H2S: Significance, Mechanisms, and Therapeutic Promise in Vascular Injury

L‐cysteine/cystathionine‐β‐synthase‐induced relaxation in mouse aorta involves a L‐serine/sphingosine‐1‐phosphate/NO pathway

Contact Info

Product

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Imbalance of Homocysteine and H₂S: Significance, Mechanisms, and Therapeutic Promise in Vascular Injury