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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

CXCL16 Is a Marker of Inflammation, Atherosclerosis, and Acute Coronary Syndromes in Humans

Michael Lehrke, MD^_*,, Segan C. Millington, BS^_*, Martina Lefterova, BS^_*, Reshmaal Gomes Cumaranatunge, MD, Philippe Szapary, MD, MSCE^,, Robert Wilensky, MD, FACC, Daniel J. Rader, MD^_*,,, Mitchell A. Lazar, MD, PhD^_* and Muredach P. Reilly, MB, MSCE^_*,,,_*

^_* Institute of Diabetes, Obesity, and Metabolism
Cardiovascular Institute
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Department of Gastroenterology, Endocrinology, and Metabolism, Ludwig-Maximilians University of Munich, Munich, Germany

Manuscript received July 10, 2006; revised manuscript received August 24, 2006, accepted September 11, 2006.

^_* Reprint requests and correspondence: Dr. Muredach P. Reilly, Cardiovascular Division, University of Pennsylvania Medical Center, 909 BRB 2/3, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6160 (Email: muredach{at}spirit.gcrc.upenn.edu).

OBJECTIVES: This study was designed to determine the association of CXCL16 with inflammation, atherosclerosis, and acute coronary syndromes.

BACKGROUND: Vascular inflammation coincides with uptake of modified lipoproteins in the pathogenesis of atherosclerosis. CXCL16 is a protein that shares scavenger receptor function, promoting uptake of modified lipids, with the activities of an inflammatory chemokine. However, the role of CXCL16 in atherosclerosis remains uncertain.

METHODS: The effect of inflammatory stimuli on CXCL16 gene and protein expression was studied in macrophages, mice, and humans, and the association of sol-CXCL16 with risk factors, atherosclerosis, and acute coronary syndromes was determined in humans.

RESULTS: Endotoxin induction of CXCL16 in human macrophages was attenuated by aspirin, nuclear factor (NF)-kappa-B inhibition and peroxisome proliferator-activated receptor (PPAR)-gamma agonists. Experimental human endotoxemia (n = 6) led to an 8-fold increase in whole-blood CXCL16 messenger ribonucleic acid (p < 0.001) and a 1.7-fold increase in soluble (sol)-CXCL16 (p < 0.001), a cleaved active chemokine. Rosiglitazone-blocked endotoxin induced sol-CXCL16 in mice (p = 0.001), and pioglitazone (n = 28), compared to placebo (n = 28), lowered plasma sol-CXCL16 in metabolic syndrome subjects (p < 0.05). In a nested case-control study of acute and chronic coronary artery disease (n = 699), sol-CXCL16 levels correlated with inflammatory and metabolic risk factors and were associated with chronic coronary artery disease (odds ratio [OR] [95% confidence interval], above vs. below median; 1.60 [1.01 to 2.58]; p = 0.04) and acute coronary syndromes (OR 2.52 [1.32 to 4.82], p = 0.005) following adjustment for established risk factors, medications, and C-reactive protein levels.

CONCLUSIONS: Our findings suggest that CXCL16 may play a pro-inflammatory role in human atherosclerosis, particularly in acute coronary syndrome.

Abbreviations and Acronyms   ACS = acute coronary syndromes   CAD = coronary artery disease   CRP = C-reactive protein   CVD = cardiovascular disease   ELISA = enzyme-linked immunosorbent assay   HDL = high-density lipoprotein   IFN = interferon   LPS = lipopolysaccharide   ox-LDL = oxidized low-density lipoprotein   RNA = ribonucleic acid   TG = triglycerides   TNF = tumor necrosis factor

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