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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)211-219
Number of pages9
JournalCardiovascular Drugs and Therapy
Volume27
Issue number3
DOIs
Publication statusPublished - Jun 2013

Fingerprint

Neutrophil Infiltration
Blood Vessels
Nitric Oxide
Neutrophils
Cholesterol
Inflammation
Interleukin-8
Rabbits
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Aptitude
Chemotaxis
Atorvastatin Calcium
Carotid Arteries
Biological Availability
Monocytes
Atherosclerosis
Leukocytes
Endothelial Cells
NCX 6560

Keywords

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

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology
  • Medicine(all)

Cite this

Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol. / Baetta, Roberta; Granata, Agnese; Miglietta, Daniela; Oliva, Francesca; Arnaboldi, Lorenzo; Bonomo, Alessandra; Ferri, Nicola; Ongini, Ennio; Bellosta, Stefano; Corsini, Alberto.

In: Cardiovascular Drugs and Therapy, Vol. 27, No. 3, 06.2013, p. 211-219.

Research output: Contribution to journalArticle

Baetta, Roberta ; Granata, Agnese ; Miglietta, Daniela ; Oliva, Francesca ; Arnaboldi, Lorenzo ; Bonomo, Alessandra ; Ferri, Nicola ; Ongini, Ennio ; Bellosta, Stefano ; Corsini, Alberto. / Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol. In: Cardiovascular Drugs and Therapy. 2013 ; Vol. 27, No. 3. pp. 211-219.
@article{25fdfaa2149c4ea29dafde02b3962b50,
title = "Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol",
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, Leukocytes, NCX-6560, Neutrophil (polymorphonuclear leukocyte [PMN]), Nitric oxide, NO-statins, Statins",
author = "Roberta Baetta and Agnese Granata and Daniela Miglietta and Francesca Oliva and Lorenzo Arnaboldi and Alessandra Bonomo and Nicola Ferri and Ennio Ongini and Stefano Bellosta and Alberto Corsini",
year = "2013",
month = "6",
doi = "10.1007/s10557-013-6445-1",
language = "English",
volume = "27",
pages = "211--219",
journal = "Cardiovascular Drugs and Therapy",
issn = "0920-3206",
publisher = "Kluwer Academic Publishers",
number = "3",

}

TY - JOUR

T1 - Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol

AU - Baetta, Roberta

AU - Granata, Agnese

AU - Miglietta, Daniela

AU - Oliva, Francesca

AU - Arnaboldi, Lorenzo

AU - Bonomo, Alessandra

AU - Ferri, Nicola

AU - Ongini, Ennio

AU - Bellosta, Stefano

AU - Corsini, Alberto

PY - 2013/6

Y1 - 2013/6

N2 - 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

AB - 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

KW - Atherosclerosis

KW - Inflammation

KW - Leukocytes

KW - NCX-6560

KW - Neutrophil (polymorphonuclear leukocyte [PMN])

KW - Nitric oxide

KW - NO-statins

KW - Statins

UR - http://www.scopus.com/inward/record.url?scp=84887360636&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887360636&partnerID=8YFLogxK

U2 - 10.1007/s10557-013-6445-1

DO - 10.1007/s10557-013-6445-1

M3 - Article

VL - 27

SP - 211

EP - 219

JO - Cardiovascular Drugs and Therapy

JF - Cardiovascular Drugs and Therapy

SN - 0920-3206

IS - 3

ER -