Involvement of 3′, 5′‐cyclic inosine monophosphate in cystathionine γ‐lyase‐dependent regulation of the vascular tone. (11th June 2021)

• Record Type: Journal Article
• Authors: Mitidieri, Emma; Vellecco, Valentina; Brancaleone, Vincenzo; Vanacore, Domenico; Manzo, Onorina L.; Martin, Emil; Sharina, Iraida; Krutsenko, Yekaterina; Monti, Maria Chiara; Morretta, Elva; Papapetropoulos, Andreas; Caliendo, Giuseppe; Frecentese, Francesco; Cirino, Giuseppe; Sorrentino, Raffaella; d'Emmanuele di Villa Bianca, Roberta; Bucci, Mariarosaria
• Is Part Of: British journal of pharmacology. Volume 178:Number 18(2021)
• Page Start: 3765
• Page End: 3782
• Publication Date: 2021-06-11
• Subjects: cyclic nucleotides -- cystathionine γ‐lyase -- gasotransmitters -- inosine 3′, 5′‐cyclic monophosphate -- phosphodiesterases -- vascular homeostasis -- vasoconstriction; Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.15516
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: l ‐cysteine or hydrogen sulfide (H2 S) donors induce a biphasic effect on precontracted isolated vessels. The contractile effect occurs within a concentration range of 10 nM to 3 μM followed by vasodilatation at 30–100 μM. Here, we have investigated the signalling involved in the H2 S‐induced contraction. Experimental Approach: Vascular response to NaHS or l ‐cysteine is evaluated on isolated precontracted with phenylephrine vessel rings harvested from wild type, cystathionine γ‐lyase (CSE −/− ), soluble guanylyl cyclase (sGCα1 −/− ) and endothelial nitric oxide synthase (eNOS −/− ) knock‐out mice. The cAMP, cGMP and inosine 3′, 5′‐cyclic monophosphate (cIMP) levels are simultaneously quantified using ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) analysis. The involvement of sGC, phosphodiesterase (PDE) 4A and PDE5 are also evaluated. Key Results: CSE‐derived H2 S‐induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H2 S contractile effect involves a transient increase of cGMP and cAMP metabolism caused by PDE5 and PDE4A, thus unmasking cIMP contracting action. The stable cell‐permeable analogue of cIMP elicits concentration‐dependent contraction on a stable background tone induced by phenylephrine. The lack of cIMP, coupled to the hypocontractility displayed by vessels harvested from CSE −/− mice, confirms that H2 S‐induced contraction involves cIMP. Conclusion and Implications: The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE‐derived H2 S that is mediated by cIMP.