Hydroxymethylglutaryl coenzyme a reductase inhibitors down-regulate chemokines and chemokine receptors in patients with coronary artery disease.
OBJECTIVE
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]-1alpha, MIP-1beta, 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-1alpha, MIP-1beta, 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-1alpha 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.
Research Institute of Internal Medicine, Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway. torgun.wahre@klinmed.uio.no
Torgun
T
Waehre
Jan K
JK
Damås
Lars
L
Gullestad
Are M
AM
Holm
Terje R
TR
Pedersen
Kjell E
KE
Arnesen
Harald
H
Torsvik
Stig S
SS
Frøland
Anne G
AG
Semb
Pål
P
Aukrust
D000328:Adult; D000368:Aged; D000069059:Atorvastatin; D018925:Chemokines / Q000032:analysis* / Q000235:genetics / Q000502:physiology*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D005260:Female; D005500:Follow-Up Studies; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000737:chemistry* / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics / Q000502:physiology*; D019707:Receptors, Chemokine / Q000032:analysis* / Q000235:genetics / Q000502:physiology*; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors
D018925:Chemokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D000069059:Atorvastatin; D019821:Simvastatin