TY - JOUR
T1 - Involvement of 3′,5′-cyclic inosine monophosphate in cystathionine γ-lyase-dependent regulation of the vascular tone
AU - Mitidieri, Emma
AU - Vellecco, Valentina
AU - Brancaleone, Vincenzo
AU - Vanacore, Domenico
AU - Manzo, Onorina L.
AU - Martin, Emil
AU - Sharina, Iraida
AU - Krutsenko, Yekaterina
AU - Monti, Maria Chiara
AU - Morretta, Elva
AU - Papapetropoulos, Andreas
AU - Caliendo, Giuseppe
AU - Frecentese, Francesco
AU - Cirino, Giuseppe
AU - Sorrentino, Raffaella
AU - d'Emmanuele di Villa Bianca, Roberta
AU - Bucci, Mariarosaria
N1 - Funding Information:
We thank Dr. Sigismondo Castaldo, Head of Biotechnologies Centre Animal Facility, Cardarelli Hospital, for hosting CSE KO mice. This work was supported by Ministry of Education, Universities and Research (MIUR) (PRIN), grant numbers 2017XZMBYX and 2017NKB2N4_004. −/− Progetti di Rilevante Interesse Nazionale
Publisher Copyright:
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2021/9
Y1 - 2021/9
N2 - Background and Purpose: l-cysteine or hydrogen sulfide (H2S) 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 H2S-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 H2S-induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H2S 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 H2S-induced contraction involves cIMP. Conclusion and Implications: The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE-derived H2S that is mediated by cIMP.
AB - Background and Purpose: l-cysteine or hydrogen sulfide (H2S) 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 H2S-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 H2S-induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H2S 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 H2S-induced contraction involves cIMP. Conclusion and Implications: The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE-derived H2S that is mediated by cIMP.
KW - cyclic nucleotides
KW - cystathionine γ-lyase
KW - gasotransmitters
KW - inosine 3′,5′-cyclic monophosphate
KW - phosphodiesterases
KW - vascular homeostasis
KW - vasoconstriction
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U2 - 10.1111/bph.15516
DO - 10.1111/bph.15516
M3 - Article
C2 - 33931865
AN - SCOPUS:85107664763
SN - 0007-1188
VL - 178
SP - 3765
EP - 3782
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 18
ER -