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

• Published in: Journal of the American College of Cardiology Vol. 41; no. 9; pp. 1460 - 1467
• Main Authors: Wæhre, Torgun, Damås, Jan K, Gullestad, Lars, Holm, Are M, Pedersen, Terje R, Arnesen, Kjell E, Torsvik, Harald, Frøland, Stig S, Semb, Anne G, Aukrust, P.ål
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 07-05-2003; Elsevier Science; Elsevier Limited
• Subjects: Adult; Aged; Anticoagulants; Atherosclerosis; Atorvastatin; Biological and medical sciences; Blood pressure; Cardiology; Cardiovascular disease; Cell culture; Chemokines; Chemokines - analysis; Chemokines - genetics; Chemokines - physiology; Cholesterol; Coronary Artery Disease - drug therapy; Coronary Artery Disease - genetics; Coronary Artery Disease - physiopathology; Cytokines; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Down-Regulation - genetics; Down-Regulation - physiology; Drug therapy; Enzymes; Female; Follow-Up Studies; Gene expression; General and cellular metabolism. Vitamins; Heart attacks; Heptanoic Acids - administration & dosage; Heptanoic Acids - pharmacology; Heptanoic Acids - therapeutic use; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Immunoassay; Leukocytes, Mononuclear - chemistry; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - physiology; Lipids; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Polymerase chain reaction; Proteins; Pyrroles - administration & dosage; Pyrroles - pharmacology; Pyrroles - therapeutic use; Receptors, Chemokine - analysis; Receptors, Chemokine - genetics; Receptors, Chemokine - physiology; RNA, Messenger - analysis; RNA, Messenger - genetics; RNA, Messenger - physiology; Simvastatin - administration & dosage; Simvastatin - pharmacology; Simvastatin - therapeutic use; Statins; Studies; Time Factors; United States > US; California; CCR; IL; MIP; RANTES; CAD; mRNA; CXCR; MCP; PBMCs; Human; Prognosis; Enzyme; Hydroxymethylglutaryl-CoA synthase; Simvastatin; Enzyme inhibitor; Cardiovascular disease; Lyases; Chemokine receptor; Statin derivative; Macrophage inflammatory protein 1; Coronary heart disease; Oxo-acid-lyases; Carbon-carbon lyases; Chemotherapy; Treatment; Follow up study; Interleukin 8; Antilipemic agent
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/S0735-1097(03)00263-8

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).
Chemokines and chemokine receptors are important mediators in atherogenesis, and we hypothesized that the statins could affect the chemokine network in CAD.
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).
Our main findings were: 1) gene expression of several chemokines (i.e., macrophage inflammatory protein [MIP]-1α, MIP-1β, 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-1α, MIP-1β, 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-1α from PBMCs in CAD patients.
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.