Modulatory effects of atorvastatin on endothelial cell-derived chemokines, cytokines, and angiogenic factors.
OBJECTIVE
To investigate the immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) by determining whether atorvastatin alters the production of specific endothelium-derived immunoactive proteins and whether its treatment effects depend on its concentration and/or inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase.


METHODS
In vitro study using a multiplexing method for protein measurement.


METHODS
University laboratory.


RESULTS
Human umbilical vein endothelial cells were cultured to approximately 80% confluence and treated with atorvastatin 1-50 microM alone or with mevalonate for 24 hours. Untreated cells served as controls. Culture-conditioned media were removed and multiplex assayed for protein content of epithelial neutrophil-activating peptide-78, interleukin-8, monocyte chemotactic protein-1, interleukin-6, interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. Atorvastatin significantly reduced the production of epithelial neutrophil-activating peptide-78, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 (p<0.001 to p<0.05) in a concentration-dependent manner without affecting basal production of interleukin-10, fibroblast growth factor, and granulocyte colony stimulating factor. The treatment effects of atorvastatin were reversed with concurrent mevalonate therapy.


CONCLUSIONS
By inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, atorvastatin lowered concentrations of several inflammatory molecules derived from basal-state endothelial cells in a concentration-dependent manner. The in vivo importance of these immunomodulatory effects needs further investigation.
Zineh
Issam
I
Department of Pharmacy Practice, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA. zineh@cop.ufl.edu
Luo
Xiaoping
X
Welder
Gregory J
GJ
Debella
Amy E
AE
Wessel
Timothy R
TR
Arant
Christopher B
CB
Schofield
Richard S
RS
Chegini
Nasser
N
D000069059:Atorvastatin; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008798:Mevalonic Acid / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*
C486263:CXCL5 protein, human; D018932:Chemokine CCL2; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007155:Immunologic Factors; D015850:Interleukin-6; D016209:Interleukin-8; D011758:Pyrroles; D016179:Granulocyte Colony-Stimulating Factor; D005346:Fibroblast Growth Factors; D000069059:Atorvastatin; D008798:Mevalonic Acid