H2S dependent and independent anti-inflammatory activity of zofenoprilat in cells of the vascular wall. (November 2016)

• Record Type: Journal Article
• Authors: Monti, Martina; Terzuoli, Erika; Ziche, Marina; Morbidelli, Lucia
• Is Part Of: Pharmacological research. Volume 113(2016:Nov.)Part A
• Page Start: 426
• Page End: 437
• Publication Date: 2016-11
• Subjects: ACEI Angiotensin-converting enzyme inhibitors -- CBS cystathionine β-synthase -- COX-2 cyclooxygenase-2 -- CSE cystathionine gamma-lyase -- eNOS endothelial NO synthase -- H2S hydrogen sulfide -- HUASM human umbilical artery smooth muscle cells -- HUVEC human umbilical vein endothelial cells -- IL-1β interlukin-1beta -- mPGES-1 microsomal prostaglandin E2synthase -- NHDF normal human dermal fibroblasts -- NO nitric oxide -- PAG propargylglycine -- PGE-2 Prostaglandin E2 -- PTGIS Prostaglandin I2 (prostacyclin) synthase -- sGC soluble guanylyl cyclase -- SMC smooth muscle cells -- VE-cadherin vascular endothelial-cadherin -- ZO-1 zonula occuldens-1; Inflammation -- H2S -- Zofenoprilat -- Vascular cells; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.09.017
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Abstract: Cardiovascular diseases as atherosclerosis are associated to an inflammatory state of the vessel wall which is accompanied by endothelial dysfunction, and adherence and activation of circulating inflammatory cells. Hydrogen sulfide, a novel cardiovascular protective gaseous mediator, has been reported to exert anti-inflammatory activity. We have recently demonstrated that the SH containing ACE inhibitor zofenoprilat, the active metabolite of zofenopril, controls the angiogenic features of vascular endothelium through H2 S enzymatic production by cystathionine gamma lyase (CSE). Based on H2 S donor/generator property of zofenoprilat, the objective of this study was to evaluate whether zofenoprilat exerts anti-inflammatory activity in vascular cells through its ability to increase H2 S availability. Here we found that zofenoprilat, in a CSE/H2 S-mediated manner, abolished all the inflammatory features induced by interlukin-1beta (IL-1β) in human umbilical vein endothelial cells (HUVEC), especially the NF-κB/cyclooxygenase-2 (COX-2)/prostanoid biochemical pathway. The pre-incubation with zofenoprilat/CSE dependent H2 S prevented IL-1β induced paracellular hyperpermeability through the control of expression and localization of cell-cell junctional markers ZO-1 and VE-cadherin. Moreover, zofenoprilat/CSE dependent H2 S reduced the expression of the endothelial markers CD40 and CD31, involved in the recruitment of circulating mononuclear cells and platelets. Interestingly, this anti-inflammatory activity was also confirmed in vascular smooth muscle cells and fibroblasts as zofenoprilat reduced, in both cell lines, proliferation, migration and COX-2 expression induced by IL-1β, but independently from the SH moiety and H2 S availability. These in vitro data document the anti-inflammatory activity of zofenoprilat on vascular cells, reinforcing the cardiovascular protective effect of this multitasking drug.