Involvement of 3′,5′‐cyclic inosine monophosphate in cystathionine γ‐lyase‐dependent regulation of the vascular tone

Abstract

Background and Purpose: L-cysteine or hydrogen sulfide (H 2 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 H 2 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 À /À ), soluble guanylyl cyclase (sGC α1 À /À ) and endothelial nitric oxide synthase (eNOS À/À ) knock-out mice. The cAMP, cGMP and inosine 3 0 ,5 0 -cyclic monophosphate (cIMP) levels are simultaneously quantified using ultraperformance 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 H 2 S-induced contraction requires an intact eNOS/NO/ sGC pathway and involves cIMP as a second messenger. H 2 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 Abbreviations: 3-MST, 3-mercaptopyruvate sulfur transferase; CAT, cysteine aspartate aminotransferase; CBS, cystathionine-β-synthase; cIMP, inosine 3 0 ,5 0 -cyclic monophosphate; cNMP, nucleotide cyclic monophosphate; CSE, cystathionine γ-lyase; ET-1, endothelin-1; ETA, endothelin-1 receptor A; ETB, endothelin-1 receptor B; H2S, hydrogen sulfide; ITP, inosine triphosphate; PLP, pyridoxal-5 0 -phosphate; UPLC, ultra-performing liquid chromatography. Emma Mitidieri and Valentina Vellecco equally contributed. Roberta d'Emmanuele di Villa Bianca and Mariarosaria Bucci equally contributed.

The Protective Effects of Ganoderic Acids from Ganoderma lucidum Fruiting Body on Alcoholic Liver Injury and Intestinal Microflora Disturbance in Mice with Excessive Alcohol Intake

“…Besides, the indolelactic acid and DL-lactate accumulate in large quantities in mice with alcohol-induced liver disease, were also decreased by GA-H intervention [ 62 , 63 ]. High-dose GA intervention also reduced the levels of glyceraldehyde and 3′,5′-cyclic inosine monophosphate in the liver, of which glyceraldehyde-derived advanced glycation end products (AGEs) trigger vascular inflammation and accelerate the development of diabetic atherosclerosis, and 3′,5′-cyclic inosine monophosphate butyrate could cause an increase in stress in phenylephrine contracted mouse aortic rings [ 64 , 65 ]. It was indicated that high-dose GA intervention could decrease the potential biomarker to ameliorate the ALD.…”

Hydrogen sulfide donor AP123 restores endothelial nitric oxide-dependent vascular function in hyperglycemia via a CREB-dependent pathway

“…To further address this hypothesis, we used aorta isolated from CSE − /− mice [65]. These mice display an impaired vascular function, a marked reduction of the endogenous hydrogen sulfide and, as also shown by others, isolated aorta rings displayed a reduced NO-dependent vasodilating response to Ach [69][70][71]. In addition, CSE − /− mice fed with a high-fat diet display a degenerative phenotype leading to leukocyte infiltration, atherosclerotic lesions and vascular stiffness [72,73].…”

Inhibition of cystathionine‐gamma lyase dampens vasoconstriction in mouse and human intracerebral arterioles

“…The effect of the CSE pharmacological inhibitor on vessel In support of our findings, a recent study showed that aortas or carotid arteries from CSE KO mice have impaired contractile responses to phenylephrine. 30 Moreover, PAG can attenuate the prostaglandin F(2α) induced vasoconstrictions in rat pulmonary arteries. 31 PAG has been reported to have some off-target effects and inhibit also other PLP-dependent enzymes such as some aminotransferases, in higher mM-range concentrations.…”