The nitric oxide-donating pravastatin, NCX 6550, inhibits cytokine release and NF-kappaB activation while enhancing PPARgamma expression in human monocyte/macrophages.

Pharmacological research : the official journal of the Italian Pharmacological Society 2010 Jul 27; In press

Amoruso A, Bardelli C, Fresu L LG, Poletti E, Palma A, Canova D DF, Zeng H HW, Ongini E, Brunelleschi S

Department of Medical Sciences, School of Medicine, University "A. Avogadro", Via Solaroli 17, 28100 Novara, Italy.

Previous studies have shown that NCX 6550 (NCX), a nitric oxide (NO)-donating pravastatin, induces anti-inflammatory effects in murine macrophage cell lines. Here, we have studied its activity in human monocyte/macrophages, by investigating cytokine release, NF-kappaB translocation and peroxisome proliferator-activated receptor gamma (PPARgamma) expression and function. For comparison, pravastatin, isosorbide-5-mononitrate (ISMN), sodium nitroprusside (SNP) and the PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ) were also tested. Monocytes and macrophages (MDM: monocyte-derived macrophages) were isolated from healthy donors; cytokine release was measured by ELISA, NF-kappaB by electrophoretic mobility shift assay and PPARgamma by Western blot and Real-Time PCR. NCX (1nM-50muM) dose-dependently inhibited phorbol 12-myristate 13-acetate (PMA)-induced TNF-alpha release from monocytes (IC(50)=240nM) and MDM (IC(50)=52nM). At 50muM, it was more effective than pravastatin, ISMN and SNP (P<0.05), but less efficient than PGJ. Similar results were obtained for IL-6. Likewise, NCX was more effective than pravastatin and the other NO donors in inhibiting PMA-induced NF-kappaB translocation in both cell types, and, at the highest concentration, significantly (P<0.05) enhanced PPARgamma protein expression in monocytes. We conclude that NCX 6550 exerts a significant anti-inflammatory activity in human monocyte/macrophages, that is also contributed by its NO donating properties, as the effects exerted by NCX are significantly higher than those evoked by pravastatin in many experimental assays. These data further indicate that the incorporation of a NO-donating moiety into a statin structure confers pharmacological properties which may translate into useful therapeutic benefits.

Keywords: nitric oxide NCX 6550 PPARgamma pravastatin