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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^,,5, Robert Wilensky, MD, FACC^,4, Daniel J. Rader, MD^_*,,,2, Mitchell A. Lazar, MD, PhD^_*,3 and Muredach P. Reilly, MB, MSCE^_*,,,1,_*

^_* Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
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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