L-cysteine/cystathionine-ß-synthase-induced relaxation in mouse aorta involves a L-serine/sphingosine-1-phosphate/NO pathway.
Br J Pharmacol
; 177(4): 734-744, 2020 02.
Article
em En
| MEDLINE
| ID: mdl-30835815
ABSTRACT
BACKGROUND AND PURPOSE:
Among the three enzymes involved in the transsulfuration pathway, only cystathionine ß-synthase (CBS) converts L-cysteine into L-serine and H2 S. 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. EXPERIMENTALAPPROACH:
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). KEYRESULTS:
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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Base de dados:
MEDLINE
Assunto principal:
Cistationina beta-Sintase
/
Cisteína
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article