title: H2S dependent and independent anti-inflammatory activity of zofenoprilat in cells of the vascular wall.
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 H2S enzymatic production by cystathionine gamma lyase (CSE). Based on H2S 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 H2S availability. Here we found that zofenoprilat, in a CSE/H2S-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 H2S 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 H2S 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 H2S availability. These in vitro data document the anti-inflammatory activity of zofenoprilat on vascular cells, reinforcing the cardiovascular protective effect of this multitasking drug.
authors.affiliation: Dept. Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Monti
authors.affiliation: Dept. Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Terzuoli
authors.affiliation: Dept. Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ziche
authors.affiliation: Dept. Life Sciences, University of Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: lucia.morbidelli@unisi.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002216:Captopril / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000099152:Cadherin 5
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D019013:CD40 Antigens; D015820:Cadherins; D002216:Captopril; D051546:Cyclooxygenase 2; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide; D053583:Interleukin-1beta; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000099152:Cadherin 5; C044958:zofenopril; C065520:zofenoprilate
keywords: H(2)S; Inflammation; Vascular cells; Zofenoprilat