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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

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, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
Institute for Surgical Research, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
Department of Cardiology, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway
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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