Involvement of 3′,5′-cyclic inosine monophosphate in cystathionine γ-lyase-dependent regulation of the vascular tone
Mitidieri E. Vellecco V. Brancaleone V. Vanacore D. Manzo O.L. Martin E. Sharina I. Krutsenko Y. Monti M.C. Morretta E. Papapetropoulos A. Caliendo G. Frecentese F. Cirino G. Sorrentino R. dEmmanuele di Villa Bianca R. Bucci M.
September 2021John Wiley and Sons Inc
British Journal of Pharmacology
2021#178Issue 183765 - 3782 pp.
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.
cyclic nucleotides , cystathionine γ-lyase , gasotransmitters , inosine 3′,5′-cyclic monophosphate , phosphodiesterases , vascular homeostasis , vasoconstriction
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Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
Department of Science, University of Basilicata, Potenza, Italy
McGovern Medical School, Department of Internal Medicine, Division of Cardiology, University of Texas Health Science Center, Houston, TX, United States
School of Science and Technology, Nazarbayev University, Astana, Kazakhstan
Department of Pharmacy, University of Salerno, Fisciano, SA, Italy
Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
Department of Pharmacy
Department of Science
McGovern Medical School
School of Science and Technology
Department of Pharmacy
Laboratory of Pharmacology
Clinical
Department of Molecular Medicine and Medical Biotechnology
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