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Research ArticleCardiovascular

Protective Effects of Novel Metal-Nonoates on the Cellular Components of the Vascular System

Martina Monti, Raffaella Solito, Luca Puccetti, Luca Pasotti, Riccardo Roggeri, Enrico Monzani, Luigi Casella and Lucia Morbidelli
Journal of Pharmacology and Experimental Therapeutics December 2014, 351 (3) 500-509; DOI: https://doi.org/10.1124/jpet.114.218404
Martina Monti
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.)
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Raffaella Solito
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.)
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Luca Puccetti
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.)
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Luca Pasotti
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.)
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Riccardo Roggeri
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.)
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Enrico Monzani
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.)
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Luigi Casella
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.)
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Lucia Morbidelli
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.)
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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.

Footnotes

    • Received July 28, 2014.
    • Accepted September 17, 2014.
  • This research was supported by the Ministry of Education, University, and Research [Grant DM 593-2000, according to article 11] and Agenzia Provinciale per lo Sviluppo Locale (APLSO, Siena) [(to Noxamet Ltd)]. M.M., L.Pa., and R.R. were Noxamet Ltd fellows.

  • dx.doi.org/10.1124/jpet.114.218404.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 3
1 Dec 2014
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Research ArticleCardiovascular

Vascular Protection Induced by Novel Metal-Nonoate

Martina Monti, Raffaella Solito, Luca Puccetti, Luca Pasotti, Riccardo Roggeri, Enrico Monzani, Luigi Casella and Lucia Morbidelli
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 500-509; DOI: https://doi.org/10.1124/jpet.114.218404

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Research ArticleCardiovascular

Vascular Protection Induced by Novel Metal-Nonoate

Martina Monti, Raffaella Solito, Luca Puccetti, Luca Pasotti, Riccardo Roggeri, Enrico Monzani, Luigi Casella and Lucia Morbidelli
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 500-509; DOI: https://doi.org/10.1124/jpet.114.218404
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