Atorvastatin affects leukocyte gene expression in dyslipidemia patients: in vivo regulation of hemostasis, inflammation and apoptosis.
BACKGROUND
The beneficial effect of HMG-CoA reductase inhibitors (statins) on coronary artery disease has been linked to mechanisms beyond their lipid-lowering effect. However the existence of direct, lipid-independent effects of statin in humans is still controversial.


OBJECTIVE
To investigate the early effect of atorvastatin on peripheral blood mononuclear cells (PBMC) in dyslipidemic patients using gene arrays.


METHODS
Eleven male patients with primary hyperlipidemia received 20 mg atorvastatin daily for 4 weeks. Blood was collected at baseline, 12 h, 36 h, 1 and 4 weeks after the start of treatment.


RESULTS
Human microarrays containing 12 650 genes were used to study the effect of atorvastatin on PBMC gene expression at all time-points. Two hundred and forty genes were significantly regulated by atorvastatin treatment, several of which are involved in hemostasis, inflammation and other processes critical to atherosclerosis. Different patterns of response over time suggested both lipid-dependent and independent effects of atorvastatin on gene expression.


CONCLUSIONS
This study demonstrates for the first time that atorvastatin regulates gene expression in PBMC in man before changes in the lipid profile are detectable in serum. Using blood leukocytes as a pharmacogenomic surrogate, we have identified new in vivo targets of atorvastatin treatment.
Wibaut-Berlaimont
V
V
Genomics and Cell Biology Units, GlaxoSmithKline, Stevenage, UK.
Randi
A M
AM
Mandryko
V
V
Lunnon
M W
MW
Haskard
D O
DO
Naoumova
R P
RP
D000328:Adult; D000924:Anticholesteremic Agents / Q000494:pharmacology; D017209:Apoptosis; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood; D016000:Cluster Analysis; D005786:Gene Expression Regulation; D006487:Hemostasis; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006949:Hyperlipidemias / Q000097:blood*; D007249:Inflammation; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011758:Pyrroles / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011973:Receptors, LDL; D012313:RNA; D002784:Cholesterol; D000069059:Atorvastatin