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CLINICAL RESEARCH

Increased Levels of Neutrophil-Activating Peptide-2 in Acute Coronary Syndromes

Possible Role of Platelet-Mediated Vascular Inflammation

Camilla Smith, MD^_*, Jan K. Damås, MD, PhD^_*, Kari Otterdal, MSc^_*, Erik Øie, MD, PhD^,, Wiggo J. Sandberg, MSc^_*, Arne Yndestad, PhD^_*, Torgun Wæhre, MD, PhD^_*, Hanne Scholz, PhD^_*, Knut Endresen, MD, PhD, Peder S. Olofsson, MD^||, Bente Halvorsen, PhD^_*, Lars Gullestad, MD, PhD, Stig S. Frøland, MD, PhD^_*,, Gøran K. Hansson, MD, PhD^|| and Pål Aukrust, MD, PhD^_*,,_*

^_* Research Institute for Internal Medicine
Institute for Surgical Research
Department of Cardiology
Section of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
^|| Department of Medicine and Centre for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

Manuscript received April 21, 2006; revised manuscript received June 6, 2006, accepted June 19, 2006.

^_* Reprint requests and correspondence: Dr. Pål Aukrust, Section of Clinical Immunology and Infectious Disease, Rikshospitalet University Hospital, N-0027 Oslo, Norway. (Email: pal.aukrust{at}rikshospitalet.no).

OBJECTIVES: We sought to investigate the role of the CXC chemokine neutrophil-activating peptide-2 (NAP-2) in atherogenesis and plaque destabilization.

BACKGROUND: Chemokines are involved in atherogenesis, but the role of NAP-2 in atherosclerotic disorders is unclear. Based on its potential pro-atherogenic properties, we hypothesized a pathogenic role for NAP-2 in coronary artery disease.

METHODS: We tested this hypothesis by differential experimental approaches including studies in patients with stable (n = 40) and unstable angina (n = 40) and healthy control subjects (n = 20).

RESULTS: The following results were discovered: 1) patients with stable, and particularly those with unstable, angina had markedly raised plasma levels of NAP-2 compared with control subjects, accompanied by increased expression of CXC receptor 2 in monocytes; 2) platelets, but also peripheral blood mononuclear cells (PBMCs), released large amounts of NAP-2 upon stimulation, with a particularly prominent PBMC response in unstable angina; 3) NAP-2 protein was detected in macrophages and smooth muscle cells of atherosclerotic plaques and in monocytes and platelets of coronary thrombi; 4) in vitro, recombinant and platelet-derived NAP-2 increased the expression of adhesion molecules and chemokines in endothelial cells; and 5) whereas aspirin reduced plasma levels of NAP-2, statin therapy increased NAP-2 with stimulating effects both on platelets and leukocytes.

CONCLUSIONS: Our findings suggest that NAP-2 has the potential to induce inflammatory responses within the atherosclerotic plaque. By its ability to promote leukocyte and endothelial cell activation, such a NAP-2-driven inflammation could promote plaque rupture and acute coronary syndromes.

Abbreviations and Acronyms   CAD = coronary artery disease   ELISA = enzyme-linked immunosorbent assay   HUVEC = human umbilical vein endothelial cell   IL = interleukin   LPS = lipopolysaccharide   MCP = monocyte chemoattractant protein   MI = myocardial infarction   NAP = neutrophil-activating peptide   oxLDL = oxidized low-density lipoprotein   PBMC = peripheral blood mononuclear cell   PCI = percutaneous coronary intervention   PHA = phytohemagglutinin   PRP = platelet-rich plasma   rh = recombinant human   SMC = smooth muscle cell   STEMI = ST-segment elevation myocardial infarction   VCAM = vascular cellular adhesion molecule

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