title: Deep proteome profiling of circulating granulocytes reveals bactericidal/permeability-increasing protein as a biomarker for severe atherosclerotic coronary stenosis.
abstract: Coronary atherosclerosis represents the major cause of death in Western societies. As atherosclerosis typically progresses over years without giving rise to clinical symptoms, biomarkers are urgently needed to identify patients at risk. Over the past decade, evidence has accumulated suggesting cross-talk between the diseased vasculature and cells of the innate immune system. We therefore employed proteomics to search for biomarkers associated with severe atherosclerotic coronary lumen stenosis in circulating leukocytes. In a two-phase approach, we first performed in-depth quantitative profiling of the granulocyte proteome on a small pooled cohort of patients suffering from chronic (sub)total coronary occlusion and matched control patients using stable isotope peptide labeling, two-dimensional LC-MS/MS and data-dependent decision tree fragmentation. Over 3000 proteins were quantified, among which 57 candidate biomarker proteins remained after stringent filtering. The most promising biomarker candidates were subsequently verified in the individual samples of the discovery cohort using label-free, single-run LC-MS/MS analysis, as well as in an independent verification cohort of 25 patients with total coronary occlusion (CTO) and 19 matched controls. Our data reveal bactericidal/permeability-increasing protein (BPI) as a promising biomarker for severe atherosclerotic coronary stenosis, being down-regulated in circulating granulocytes of CTO patients.
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute of Pharmaceutical Sciences, Utrecht University and Netherlands Proteomics Centre, Utrecht, The Netherlands.
authors.forename: Onno B
authors.initials: OB
authors.lastname: Bleijerveld
authors.forename: Patrick
authors.initials: P
authors.lastname: Wijten
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cappadona
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: McClellan
authors.forename: Ayse N
authors.initials: AN
authors.lastname: Polat
authors.forename: Reinout
authors.initials: R
authors.lastname: Raijmakers
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Sels
authors.forename: Loes
authors.initials: L
authors.lastname: Colle
authors.forename: Simona
authors.initials: S
authors.lastname: Grasso
authors.forename: Henk W
authors.initials: HW
authors.lastname: van den Toorn
authors.forename: Bas
authors.initials: B
authors.lastname: van Breukelen
authors.forename: Andrew
authors.initials: A
authors.lastname: Stubbs
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Arjen
authors.initials: A
authors.lastname: Scholten
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000097:blood*; D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins; D002469:Cell Separation; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood*; D023921:Coronary Stenosis / Q000097:blood*; D006098:Granulocytes / Q000378:metabolism*; D006801:Humans; D020543:Proteome
chemical_list: D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; D001798:Blood Proteins; D020543:Proteome; C021623:bactericidal permeability increasing protein