Clinical Evidence of a Protective Role for CXCL5 in Coronary Artery Disease Progression in the Elderly

Abstract

Advanced age is associated with higher risk for cardiovascular disease and poor prognosis in patients with established cardiovascular disease. Moreover, the pathophysiology underlying CAD in older individuals may be distinct from that in younger individuals. Therefore, we utilized candidate biomarker and systems biology approaches to improve our understanding of the pathogenesis and progression of CAD in older adults. We enrolled individuals who were at least 65 years of age and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating biomarkers of inflammation and mRNA expression levels in peripheral blood mononuclear cells were quantified. We identified 553 genes (FDR<7%) that correlated with CAD severity and consisted of clusters of inflammatory genes, p38 MAPK signaling genes, and leukocyte activation, consistent with a heightened inflammatory state. The enriched expression of genes related to leukocyte activation suggested that inflammation mediated by the mobilization of leukocytes impacts the CAD gene expression signature and perhaps the extent of disease. We used the functional gene expression analysis to identify candidate circulating molecules that could propagate the CAD‐associated inflammatory response through recruitment of leukocytes to the area of injury. One class of molecules known to recruit leukocytes is the ELR+‐CXCL chemokine family. One chemokine of interest was the leukocyte‐derived CXCL5 (initially described as ENA‐78) in particular due to its ability to activate p38 and its proposed role as a key mediator in the formation of a inflammatory microenvironment in cancer and tuberculosis. Therefore, we hypothesized that the CXCL5 levels would be higher in patients with obstructive CAD and with increased CAD severity. We performed the analyses on CXCL5 plasma levels and surprisingly we observed a negative association of CXCL5 levels with CAD at an odds ratio (OR) of 0.46 (95% confidence interval: 0.27 − 0.75). Controlling for known covariates including gender and statin use, the OR was not significantly affected, 0.54 (0.30 − 0.91), consistent with a protective role for CXCL5 in coronary atherosclerosis. Our data are consistent with a recent study in a mouse model of atherosclerosis that demonstrated that CXCL5 is protective in atherosclerosis by limiting foam cell accumulation at the site of injury (doi:10.1172/JCI66580). It is unclear if CXCL5 limits foam cell formation in humans, however our clinical findings are consistent with the emerging link between chemokines and foam cell formation and represents a new therapeutic target for CAD.Support or Funding Information5R01HL065619‐13 National Heart, Lung, and Blood Institute