title: Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced antiproliferative and antiinflammatory properties.
abstract: Inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, namely statins, exert pleiotropic actions beyond lipid-lowering effects. Their pharmacological activity on atherosclerotic plaque stability and vascular inflammation appears to be mediated, at least in part, by nitric oxide (NO). With the aim of enhancing the nonlipid-lowering properties of selected statins, we introduced a NO-releasing moiety into the structure of pravastatin (NCX 6550) and fluvastatin (NCX 6553). NO release was evaluated as nitrosylhemoglobin adduct formation by using EPR spectroscopy in rat blood. Both compounds produced a linear time-dependent increase in nitrosylhemoglobin formation, which is consistent with slow NO release kinetics. In PC12 cells, unlike their native statins, both compounds stimulated cGMP formation (NCX 6550, EC(50) = 2.3 +/- 0.2 microM; NCX 6553, EC(50) = 2.7 +/- 0.2 microM). Moreover, NCX 6550 potently inhibited cell proliferation in rat aortic smooth muscle cells (IC(50) = 2.2 +/- 0.3 microM) with a mechanism that involved both the polyamine and HMG-CoA reductase signaling pathways. Hence, mevalonate or putrescine partially reverted the effects of NCX 6550 and their combination was fully effective. In RAW 264.7 murine macrophage cells stimulated with lipopolysaccharide (1 microg/ml), NCX 6550, but not pravastatin, significantly decreased inducible NO synthase and cyclooxygenase-2 protein expression as well as nitrite accumulation. All together, the data show that the previously undescribed NO-releasing statins retain HMG-CoA reductase inhibitory activity and release bioactive NO slowly. Among the additional properties, compared with native statins, the NO-releasing statins show enhanced antiinflammatory effects. Thus, NO-releasing statins represent an interesting class of drugs having potential in the therapy of disorders associated with endothelial dysfunction and vascular inflammation.
authors.affiliation: Nicox Research Institute, Via Ariosto 21, 20091 Bresso, Milan, Italy. ongini@2nicox.it
authors.forename: Ennio
authors.initials: E
authors.lastname: Ongini
authors.forename: Francesco
authors.initials: F
authors.lastname: Impagnatiello
authors.forename: Albino
authors.initials: A
authors.lastname: Bonazzi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Guzzetta
authors.forename: Mirco
authors.initials: M
authors.lastname: Govoni
authors.forename: Angela
authors.initials: A
authors.lastname: Monopoli
authors.forename: Piero
authors.initials: P
authors.lastname: Del Soldato
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ignarro
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000077340:Fluvastatin; D006454:Hemoglobins / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D017035:Pravastatin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D005229:Fatty Acids, Monounsaturated; D006454:Hemoglobins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D009573:Nitrites; C008657:nitrosyl hemoglobin; D009569:Nitric Oxide; D000077340:Fluvastatin; D006152:Cyclic GMP; D017035:Pravastatin