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CLINICAL RESEARCH

Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease

Torgun Wæhre, MD^*,*, Jan K. Damås, MD, PhD^*, Lars Gullestad, MD, PhD, Are M. Holm, MD^*, Terje R. Pedersen, MD, PhD^||, Kjell E. Arnesen, MD^¶, Harald Torsvik, MD, PhD, Stig S. Frøland, MD, PhD^*, Anne G. Semb, MD, PhD^|| and P.ål Aukrust, MD, PhD^*

^* Research Institute of Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway
Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway
Section of Clinical Immunology and Infectious Diseases, Rikshospitalet University Hospital, Oslo, Norway
Department of Cardiology, Bærum Hospital, Bærum, Norway
^|| Department of Cardiology, Aker University Hospital, Oslo, Norway
^¶ Department of Medicine, Akershus University Hospital, Lørenskog, Norway

Manuscript received September 25, 2002; revised manuscript received December 13, 2002, accepted January 24, 2003.

^* Reprint requests and correspondence: Dr. Torgun Wæhre, Research Institute of Internal Medicine, Rikshospitalet University Hospital, N-0027 Oslo, Norway.
torgun.wahre{at}klinmed.uio.no

OBJECTIVES: We sought to investigate whether the activation of the chemokine network observed in patients with coronary artery disease (CAD) could be modified by treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins).

BACKGROUND: Chemokines and chemokine receptors are important mediators in atherogenesis, and we hypothesized that the statins could affect the chemokine network in CAD.

METHODS: Thirty CAD patients without previous statin therapy were randomized to receive atorvastatin (80 mg/day, n = 15) or simvastatin (20 mg/day, n = 15). Peripheral blood mononuclear cells (PBMCs) and plasma were obtained at baseline and after six months of statin therapy. Messenger ribonucleic acid (mRNA) expression of chemokines and chemokine receptors in PBMCs was analyzed by ribonuclease protection assay and real-time reverse-transcription polymerase chain reaction. Chemokines were also examined in the supernatants from unstimulated and lipopolysaccharide-stimulated PBMCs (and in plasma).

RESULTS: Our main findings were: 1) gene expression of several chemokines (i.e., macrophage inflammatory protein [MIP]-1, MIP-1ß, and interleukin [IL]-8) and chemokine receptors (i.e., CC chemokine receptor [CCR]1, CCR2, CCR4, and CCR5) was markedly increased among CAD patients compared with healthy control subjects; 2) treatment with atorvastatin and simvastatin markedly reduced the mRNA levels of some of these chemokines (i.e., MIP-1, MIP-1ß, IL-8) and receptors (i.e., CCR1 and CCR2), with the most pronounced effect in the atorvastatin group; and 3) statin therapy reduced the spontaneous release of IL-8 and MIP-1 from PBMCs in CAD patients.

CONCLUSIONS: This study demonstrates a down-regulatory effect of statins on the chemokine network in CAD patients, possibly contributing to the beneficial effects of statins in this disorder.

Abbreviations and Acronyms   CAD = coronary artery disease   CCR = CC chemokine receptor   CXCR = CXC chemokine receptor   IL = interleukin   MCP = monocyte chemoattractant protein   MIP = macrophage inflammatory protein   mRNA = messenger ribonucleic acid   PBMCs = peripheral blood mononuclear cells   RANTES = regulated upon activation, normally T cell expressed and secreted

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