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

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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.

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Acknowledgments

We are indebted to Dr. Alessandro Balsamo and Dr. Cristian Salvatore Appari for their assistance with the in vivo work. We thank Dr. Carola Buccellati for precious guidance on neutrophil isolation, Dr. Giampaolo Tibolla and Mrs. Patrizia Uboldi for kindly providing HUVEC cells, and Dr. Emanuela Corsini for helpful advice on IL-8 measurement. Finally, we thank Dr. Angela Monopoli for fruitful discussion.

R.B. was supported by a grant from the Fondo per gli Investimenti della Ricerca di Base (FIRB) CHEM-PROFARMA-NET.

Disclosure

This work was supported in part by a research grant from Nicox Research Intitute, Bresso (Milan), Italy, the manufacturer of the NO-donating compound under study. A.C. has received research grants and has been a consultant for NiCox Research Intitute. D.M., F.O., and E.O. are employees of Nicox Research Intitute.

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Author notes

  1. Roberta Baetta

    Present address: Laboratorio di Biologia Cellulare e Biochimica dell’Aterotrombosi, Centro Cardiologico Monzino, Via C. Parea 4, 20138, Milan, Italy

Authors and Affiliations

  1. Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan, Via Balzaretti 9, 20133, Milan, Italy

    Roberta Baetta, Agnese Granata, Lorenzo Arnaboldi, Alessandra Bonomo, Nicola Ferri, Stefano Bellosta & Alberto Corsini

  2. Nicox Research Institute, Via Ludovico Ariosto 21, 20091, Bresso, Milan, Italy

    Daniela Miglietta, Francesca Oliva & Ennio Ongini

  3. Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy

    Roberta Baetta

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Baetta, R., Granata, A., Miglietta, D. et al. Nitric Oxide-Donating Atorvastatin Attenuates Neutrophil Recruitment During Vascular Inflammation Independent of Changes in Plasma Cholesterol. Cardiovasc Drugs Ther 27, 211–219 (2013). https://doi.org/10.1007/s10557-013-6445-1

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