Receptor activator of NF-κB ligand (RANKL) increases the release of neutrophil products associated with coronary vulnerability

Alessandra Quercioli; François Mach; Maria Bertolotto; Sébastien Lenglet; Nicolas Vuilleumier; Katia Galan; Sabrina Pagano; Vincent Braunersreuther; Graziano Pelli; Vito Pistoia; Giovanna Bianchi; Giuseppe Cittadini; Giorgio Luciano Viviani; Aldo Pende; Pascale Roux-Lombard; Aurélien Thomas; Christian Staub; Osman Ratib; Franco Dallegri; Thomas Helmut Schindler; Fabrizio Montecucco

doi:10.1160/TH11-05-0324

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(01): 124-139
DOI: 10.1160/TH11-05-0324

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Receptor activator of NF-κB ligand (RANKL) increases the release of neutrophil products associated with coronary vulnerability

Authors

Alessandra Quercioli^*

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
François Mach^*

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Maria Bertolotto

²First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Italy
Sébastien Lenglet

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Nicolas Vuilleumier

³Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Switzerland
Katia Galan

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Sabrina Pagano

³Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Switzerland
Vincent Braunersreuther

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Graziano Pelli

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Vito Pistoia

⁴Laboratory of Oncology, G. Gaslini Scientific Institute, Genoa, Italy
Giovanna Bianchi

⁴Laboratory of Oncology, G. Gaslini Scientific Institute, Genoa, Italy
Giuseppe Cittadini

⁵Department of Radiology, San Martino Hospital, University of Genoa, Genoa, Italy
Giorgio Luciano Viviani

⁶Department of Internal Medicine, Adult Diabetes Centre, University of Genoa, Italy
Aldo Pende

²First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Italy
Pascale Roux-Lombard

³Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Switzerland

⁷Division of Immunology and Allergy, Department of Internal Medicine, Geneva University Hospital and University of Geneva, Switzerland
Aurélien Thomas

⁸Unit of Toxicology, CURML, Geneva University Hospitals, Geneva, Switzerland
Christian Staub

⁸Unit of Toxicology, CURML, Geneva University Hospitals, Geneva, Switzerland
Osman Ratib

⁹Division of Nuclear Medicine, Geneva University Hospital, Geneva, Switzerland
Franco Dallegri

²First Medical Clinic, Laboratory of Phagocyte Physiopathology and Inflammation, Department of Internal Medicine, University of Genoa, Italy
Thomas Helmut Schindler^#

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland
Fabrizio Montecucco^#

¹ Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland

Abstract

Summary

The “blood vulnerability”, resulting from the complex balance between serum molecules and inflammatory cell atherosclerotic activities, is a major determinant in the evaluation of the “global patient cardiovascular vulnerability”. In the present study, we focused on the role of the soluble receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL, a potential marker of coronary calcification and vulnerability) in the release of neutrophilic proteases. Then, the association between these mediators and the degree of coronary calcification (assessed by coronary calcium score [CCS]) was investigated in 20 subjects (aged ≥65 years) asymptomatic for cardiovascular disease. Results showed that RANKL dose-dependently induced matrix metalloprotease (MMP)-8 and MMP-9 release from human primary neutrophils cultured in Teflon dishes (suspension condition, mimicking cells circulating in the blood stream). Conversely, when adherent to polystyrene, neutrophils became unresponsive to RANKL. RANKL did not influence the release of other neutrophilic products in suspension and adherence cultures as well as neutrophil migration. RANKL-induced release of MMPs was dependent on the activation of defined intracellular signalling pathways (PI3K/Akt and ERK1/2). In asymptomatic subjects, serum levels of RANKL, MMP-8 and MMP-9 positively correlated with CCS, reflecting a potential relationship between circulating RANKL and coronary calcification. In conclusion, RANKL increased the release of neutrophilic products potentially related to the “blood” vulnerability via defined intracellular pathways. Serum levels of RANKL might represent a potential biomarker of coronary calcification and related cardiovascular risk.

Keywords

Atherosclerosis - matrix metalloproteinases - leukocyte function/activation

Full Text

References

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