Nitric oxide (NO)-releasing statin derivatives, a class of drugs showing enhanced antiproliferative and antiinflammatory properties

摘要: 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 enhancing nonlipid-lowering properties selected we introduced a NO-releasing moiety into structure pravastatin (NCX 6550) fluvastatin 6553). NO release was evaluated as nitrosylhemoglobin adduct formation using EPR spectroscopy rat blood. Both compounds produced linear time-dependent increase formation, which is consistent with slow kinetics. In PC12 cells, unlike their native both stimulated cGMP 6550, EC50 = 2.3 ± 0.2 μM; NCX 6553, 2.7 μM). Moreover, 6550 potently inhibited cell proliferation aortic smooth muscle cells (IC50 2.2 0.3 μM) mechanism that involved polyamine HMG-CoA reductase signaling pathways. Hence, mevalonate or putrescine partially reverted effects combination fully effective. RAW 264.7 murine macrophage lipopolysaccharide (1 μg/ml), but not pravastatin, significantly decreased inducible synthase cyclooxygenase-2 protein expression well nitrite accumulation. All together, data show previously undescribed statins retain inhibitory bioactive slowly. Among additional properties, compared enhanced antiinflammatory Thus, represent an interesting class drugs having potential therapy disorders associated endothelial dysfunction inflammation.