ORIGINAL ARTICLE

Cardiovascular Drugs and Therapy

, Volume 27, Issue 3, pp 211-219

First online:

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

  • Roberta BaettaAffiliated withDipartimento di Scienze Farmacologiche e Biomolecolari, University of MilanDipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di MilanoLaboratorio di Biologia Cellulare e Biochimica dell’Aterotrombosi, Centro Cardiologico Monzino Email author 
  • , Agnese GranataAffiliated withDipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan
  • , Daniela MigliettaAffiliated withNicox Research Institute
  • , Francesca OlivaAffiliated withNicox Research Institute
  • , Lorenzo ArnaboldiAffiliated withDipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan
  • , Alessandra BonomoAffiliated withDipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan
  • , Nicola FerriAffiliated withDipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan
  • , Ennio OnginiAffiliated withNicox Research Institute
  • , Stefano BellostaAffiliated withDipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan
    • , Alberto CorsiniAffiliated withDipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan

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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