Cardiovascular Drugs and Therapy

, Volume 27, Issue 3, pp 211–219

Nitric Oxide-Donating Atorvastatin Attenuates Neutrophil Recruitment During Vascular Inflammation Independent of Changes in Plasma Cholesterol

  • Roberta Baetta
  • Agnese Granata
  • Daniela Miglietta
  • Francesca Oliva
  • Lorenzo Arnaboldi
  • Alessandra Bonomo
  • Nicola Ferri
  • Ennio Ongini
  • Stefano Bellosta
  • Alberto Corsini
ORIGINAL ARTICLE

Abstract

Purpose

Polymorphonuclear neutrophils, the first leukocytes to infiltrate the inflamed tissue, can make important contributions to vascular inflammatory processes driving the development of atherosclerosis. We herein investigated the effects of atorvastatin and NCX 6560 (a nitric oxide (NO)-donating atorvastatin derivative that has completed a successful phase 1b study) on neutrophilic inflammation in carotid arteries of normocholesterolemic rabbits subjected to perivascular collar placement.

Methods

Atorvastatin or NCX 6560 were administered orally (5 mg/kg/day or equimolar dose) to New Zealand White rabbits for 6 days, followed by collar implantation 1 h after the last dose. Twenty-four hours later carotids were harvested for neutrophil quantification by immunostaining.

Results

Treatment with NCX 6560 was associated with a lower neutrophil infiltration (−39.5 %), while atorvastatin did not affect neutrophil content. The result was independent of effects on plasma cholesterol or differences in atorvastatin bioavailability, which suggests an important role of NO-related mechanisms in mediating this effect. Consistent with these in vivo findings, in vitro studies showed that NCX 6560, as compared to atorvastatin, had greater inhibitory activity on processes involved in neutrophil recruitment, such as migration in response to IL-8 and IL-8 release by endothelial cells and by neutrophils themselves. Pretreatment with NCX 6560, but not with atorvastatin, reduced the ability of neutrophil supernatants to promote monocyte chemotaxis, a well-known pro-inflammatory activity of neutrophils.

Conclusion

Experimental data suggest a potential role of NO-releasing statins in the control of the vascular inflammatory process mediated by polymorphonuclear neutrophils.

Keywords

Atherosclerosis Inflammation Neutrophil (polymorphonuclear leukocyte [PMN]) Leukocytes Nitric oxide Statins NO-statins NCX-6560 

Supplementary material

10557_2013_6445_MOESM1_ESM.docx (107 kb)
ESM 1(DOCX 106 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Roberta Baetta
    • 1
    • 3
    • 4
  • Agnese Granata
    • 1
  • Daniela Miglietta
    • 2
  • Francesca Oliva
    • 2
  • Lorenzo Arnaboldi
    • 1
  • Alessandra Bonomo
    • 1
  • Nicola Ferri
    • 1
  • Ennio Ongini
    • 2
  • Stefano Bellosta
    • 1
  • Alberto Corsini
    • 1
  1. 1.Dipartimento di Scienze Farmacologiche e BiomolecolariUniversity of MilanMilanItaly
  2. 2.Nicox Research InstituteBressoItaly
  3. 3.Dipartimento di Scienze Farmacologiche e BiomolecolariUniversità degli Studi di MilanoMilanItaly
  4. 4.Laboratorio di Biologia Cellulare e Biochimica dell’AterotrombosiCentro Cardiologico MonzinoMilanItaly

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