Biphasic effect of HMG-CoA reductase inhibitor, pitavastatin, on vascular endothelial cells and angiogenesis.
BACKGROUND
HMG-CoA reductase inhibitors (statins) have pleiotropic effects beyond their cholesterol-lowering effect. However, consensus on the effect of statins on endothelial cells and angiogenesis has not yet been reached.


RESULTS
The effects of pitavastatin on the migration, proliferation and viability of human epidermal microvessel endothelial cells (HMVECs) were examined using scratch assay, chemotaxis chamber, bromodeoxyuridine incorporation, trypan blue dye exclusion test, and nuclear DNA staining. Pitavastatin enhanced the migration, proliferation and viability of HMVECs at a low concentration (0.01 micromol/L) but inhibited them at high concentration (1 micromol/L). The inhibitory effect on cell viability by high concentration of pitavastatin was recovered by geranylgeranyl pyrophosphate, but the effect on migration and proliferation was not. The cell activating effect of a low concentration of pitavastatin was reversed by both farnesyl pyrophosphate and geranylgeranyl pyrophosphate. A quail chorioallantoic membrane assay showed that high concentration (1 micromol/L) of pitavastatin reduced fibroblast growth factor-2-induced angiogenesis, whereas low concentration (0.3 micromol/L) tended to increase angiogenesis.


CONCLUSIONS
Pitavastatin has a biphasic effect on HMVECs and on angiogenesis through at least 2 different pathways that include the mevalonate pathway.
Katsumoto
Masayuki
M
Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Japan.
Shingu
Tetsuji
T
Kuwashima
Rieko
R
Nakata
Atsunori
A
Nomura
Shuichi
S
Chayama
Kazuaki
K
D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D011756:Diphosphates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008833:Microcirculation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D012867:Skin / Q000098:blood supply
D011756:Diphosphates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; C108475:pitavastatin