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- Title
Epithelial Neutrophil-Activating Peptide (ENA-78), Acute Coronary Syndrome Prognosis, and Modulatory Effect of Statins.
- Authors
Zineh, Issam; Beitelshees, Amber L.; Welder, Gregory J.; Wei Hou; Chegini, Nasser; Wu, Jun; Cresci, Sharon; Province, Michael A.; Spertus, John A.
- 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 2156 G.C polymorphism (rs352046) with 3-year allcause 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-1b 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-1b-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.
- Subjects
STATINS (Cardiovascular agents); NEUTROPHILS; INFLAMMATION; CHEMOKINES; CORONARY disease; PEPTIDE hormones; GENE expression; GENETIC regulation; PHARMACODYNAMICS
- Publication
PLoS ONE, 2008, Vol 3, Issue 9, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0003117