title: Epithelial neutrophil-activating peptide (ENA-78), acute coronary syndrome prognosis, and modulatory effect of statins.
abstract: Endothelial inflammation with chemokine involvement contributes to acute coronary syndromes (ACS). We tested the hypothesis that variation in the chemokine gene CXCL5, which encodes epithelial neutrophil-activating peptide (ENA-78), is associated with ACS prognosis. We also investigated whether statin use, a potent modulator of inflammation, modifies CXCL5's association with outcomes and characterized the in vitro effect of atorvastatin on endothelial ENA-78 production. Using a prospective cohort of ACS patients (n = 704) the association of the CXCL5 -156 G>C polymorphism (rs352046) with 3-year all-cause mortality was estimated with hazard ratios (HR). Models were stratified by genotype and race. To characterize the influence of statins on this association, a statin*genotype interaction was tested. To validate ENA-78 as a statin target in inflammation typical of ACS, endothelial cells (HUVECs) were treated with IL-1beta and atorvastatin with subsequent quantification of CXCL5 expression and ENA-78 protein concentrations. C/C genotype was associated with a 2.7-fold increase in 3-year all-cause mortality compared to G/G+G/C (95%CI 1.19-5.87; p = 0.017). Statins significantly reduced mortality in G/G individuals only (58% relative risk reduction; p = 0.0009). In HUVECs, atorvastatin dose-dependently decreased IL-1beta-stimulated ENA-78 concentrations (p<0.0001). Drug effects persisted over 48 hours (p<0.01). CXCL5 genotype is associated with outcomes after ACS with potential statin modification of this effect. Atorvastatin lowered endothelial ENA-78 production during inflammation typical of ACS. These findings implicate CXCL5/ENA-78 in ACS and the statin response.
authors.affiliation: Center for Pharmacogenomics and Department of Pharmacy Practice, University of Florida College of Pharmacy, Gainesville, Florida, United States of America. zineh@cop.ufl.edu
authors.forename: Issam
authors.initials: I
authors.lastname: Zineh
authors.forename: Amber L
authors.initials: AL
authors.lastname: Beitelshees
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Welder
authors.forename: Wei
authors.initials: W
authors.lastname: Hou
authors.forename: Nasser
authors.initials: N
authors.lastname: Chegini
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Sharon
authors.initials: S
authors.lastname: Cresci
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.forename: John A
authors.initials: JA
authors.lastname: Spertus