The nitric oxide-donating pravastatin, NCX 6550, inhibits cytokine release and NF-κB activation while enhancing PPARγ expression in human monocyte/macrophages.
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-κB translocation and peroxisome proliferator-activated receptor γ (PPARγ) expression and function. For comparison, pravastatin, isosorbide-5-mononitrate (ISMN), sodium nitroprusside (SNP) and the PPARγ ligand 15-deoxy-Δ(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-κB by electrophoretic mobility shift assay and PPARγ by Western blot and Real-Time PCR. NCX (1 nM-50 μM) dose-dependently inhibited phorbol 12-myristate 13-acetate (PMA)-induced TNF-α release from monocytes (IC(50)=240 nM) and MDM (IC(50)=52 nM). At 50 μM, 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-κB translocation in both cell types, and, at the highest concentration, significantly (P<0.05) enhanced PPARγ 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.
Amoruso
Angela
A
Department of Medical Sciences, School of Medicine, University A. Avogadro, Via Solaroli 17, 28100 Novara, Italy.
Bardelli
Claudio
C
Fresu
Luigia Grazia
LG
Poletti
Elisa
E
Palma
Alessandra
A
Federici Canova
Donata
D
Zeng
Hua Wu
HW
Ongini
Ennio
E
Brunelleschi
Sandra
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D017035:Pravastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C516976:1,2,6,7,8,8a-hexahydro-beta,delta,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid 4-(nitrooxy)butyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D009566:Nitrates; D020030:Nitric Oxide Donors; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009569:Nitric Oxide; D017035:Pravastatin