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
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Figure 1 Gene expression of four chemokines (A), four CC chemokine receptors (CCR) (B), and three CXC chemokine receptors (CXCR) (C) in healthy controls (CTR; n = 15 in A and B and n = 7 in C) and coronary artery disease (CAD) patients (CAD; n = 30) before statin therapy. Horizontal lines indicate median values. (A and B) Gene expression is assessed by ribonuclease protection assay, normalized to the house-keeping genes glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), and data are presented as percentage of GAPDH expression. (C) Gene expression is assessed by quantitative reverse transcription-polymerase chain reaction and normalized to beta-actin expression. IL = interleukin; MIP = macrophage inflammatory protein; mRNA = messenger ribonucleic acid; RANTES = regulated upon activation, normally T cell expressed and secreted.
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Figure 2 Representative ribonuclease protection assay of chemokines in peripheral blood mononuclear cells from one control subject (CTR) and one coronary artery disease (CAD) patient at baseline and after six months of atorvastatin therapy. The left lane shows the positive control with all chemokines represented on the hCK5 probe. Ltn = lymphotactin; IP-10 = interferon-gamma inducible protein-10; I-309 = inducible-309; MCP = monocyte chemoattractant protein; MIP = macrophage inflammatory protein; RANTES = regulated upon activation, normally T cell expressed and secreted. House-keeping (control) genes: rpL32 = ribosomal protein 32; GAPDH = glyceraldehyde-3-phosphate dehydrogenase.
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Figure 3 Gene expression of macrophage inflammatory protein (MIP)-1 (A), MIP-1ß (B), interleukin (IL)-8 (C), CC chemokine receptor (CCR)1 (D), and CCR2 (E) from coronary artery disease patients at baseline and after six months of atorvastatin therapy (open circles; n = 15) or simvastatin (solid circles; n = 15). Gene expression is normalized to the house-keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Data are presented as the mean value ± SEM. *p < 0.05 and **p < 0.01 versus baseline values. #p < 0.01 comparing differences in changes between the two treatment groups. mRNA = messenger ribonucleic acid.
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Figure 4 Protein levels of macrophage inflammatory protein (MIP)-1 (A), interleukin (IL)-8 (B), and monocyte chemoattractant protein (MCP)-1 (C) in supernatants from unstimulated, cryopreserved peripheral blood mononuclear cells (PBMCs) collected before (baseline) and after six months of atorvastatin therapy in 13 coronary artery disease patients. The PBMCs were cultured for 20 h. Data are presented as the mean value ± SD. *p < 0.05 versus baseline.
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