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

Abstract

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.