title: Protective effects of novel metal-nonoates on the cellular components of the vascular system.
abstract: At the cardiovascular level, nitric oxide (NO) controls smooth muscle functions, maintains vascular integrity, and exerts an antihypertensive effect. Metal-nonoates are a recently discovered class of NO donors, with NO release modulated through the complexation of the N-aminoethylpiperazine N-diazeniumdiolate ligand to metal ions, and thus representing a significant innovation with respect to the drugs traditionally used. In this study, we characterized the vascular protective effects of the most effective compound of this class, Ni(PipNONO)Cl, compared with the commercial N-diazeniumdiolate group derivate, diethylenetriamine/nitric oxide (DETA/NO). Ni(PipNONO)Cl induced a concentration-dependent relaxation of precontracted rat aortic rings. The ED50 was 0.67 µM, compared with 4.3 µM obtained with DETA/NO. When tested on cultured microvascular endothelial cells, Ni(PipNONO)Cl exerted a protective effect on the endothelium, promoting cell proliferation and survival in the picomolar range. The administration of Ni(PipNONO)Cl to vascular smooth muscle cells reduced the cell number, promoting their apoptosis at a high concentration (10 µM). Inhibition of smooth muscle cell migration, a hallmark of atherosclerosis, was accompanied by cytoskeletal rearrangement and loss of lamellipodia. When added to isolated platelets, Ni(PipNONO)Cl significantly reduced ADP-induced aggregation. Since atherosclerosis is accompanied by an inflammatory environment, cultured endothelial cells were exposed to interleukin (IL)-1β. In the presence of IL-1β, Ni(PipNONO)Cl inhibited cyclooxygenase-2 and inducible nitric oxide synthase upregulation, and reduced endothelial permeability and the platelet and monocyte adhesion markers CD31 and CD40 at the plasma membrane. Overall, these data indicate that Ni(PipNONO)Cl exerts vascular protective effects relevant for vascular dysfunction and prevention of atherosclerosis and thrombosis.
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.).
authors.forename: Martina
authors.initials: M
authors.lastname: Monti
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.).
authors.forename: Raffaella
authors.initials: R
authors.lastname: Solito
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.).
authors.forename: Luca
authors.initials: L
authors.lastname: Puccetti
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.).
authors.forename: Luca
authors.initials: L
authors.lastname: Pasotti
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.).
authors.forename: Riccardo
authors.initials: R
authors.lastname: Roggeri
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.).
authors.forename: Enrico
authors.initials: E
authors.lastname: Monzani
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.).
authors.forename: Luigi
authors.initials: L
authors.lastname: Casella
authors.affiliation: Department of Life Sciences (M.M., R.S., L.M.) and Division of Hematology, Atherothrombosis Center (L.Pu.), University of Siena, Siena, Italy; Department of Chemistry, University of Pavia, Pavia, Italy (L.Pa., E.M., L.C.); and Noxamet Ltd., Milan, Italy (M.M., L.Pa., R.R., E.M., L.C., L.M.) lucia.morbidelli@unisi.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morbidelli
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D002316:Cardiotonic Agents; D020030:Nitric Oxide Donors