title: Receptor activator of NF- κB ligand (RANKL) increases the release of neutrophil products associated with coronary vulnerability.
abstract: 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.
authors: Division of Cardiology, Geneva University Hospital, Faculty of Medicine, Foundation for Medical Researches, Geneva, Switzerland.
authors: Alessandra
authors: A
authors: Quercioli
authors: François
authors: F
authors: Mach
authors: Maria
authors: M
authors: Bertolotto
authors: Sébastien
authors: S
authors: Lenglet
authors: Nicolas
authors: N
authors: Vuilleumier
authors: Katia
authors: K
authors: Galan
authors: Sabrina
authors: S
authors: Pagano
authors: Vincent
authors: V
authors: Braunersreuther
authors: Graziano
authors: G
authors: Pelli
authors: Vito
authors: V
authors: Pistoia
authors: Giovanna
authors: G
authors: Bianchi
authors: Giuseppe
authors: G
authors: Cittadini
authors: Giorgio Luciano
authors: GL
authors: Viviani
authors: Aldo
authors: A
authors: Pende
authors: Pascale
authors: P
authors: Roux-Lombard
authors: Aurélien
authors: A
authors: Thomas
authors: Christian
authors: C
authors: Staub
authors: Osman
authors: O
authors: Ratib
authors: Franco
authors: F
authors: Dallegri
authors: Thomas Helmut
authors: TH
authors: Schindler
authors: Fabrizio
authors: F
authors: Montecucco
mesh_terms: D000328:Adult; D002114:Calcinosis; D002118:Calcium / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000378:metabolism; D015331:Cohort Studies; D003331:Coronary Vessels / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D053245:RANK Ligand; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D002118:Calcium