Pravastatin induces rat aortic endothelial cell proliferation and migration via activation of PI3K/Akt/mTOR/p70 S6 kinase signaling.
The HMG-CoA reductase inhibitors (statins) have been shown to exert several vascular protective effects that are not related to changes in cholesterol profile, and these effects of statins are partly caused by the activation of angiogenesis. Endothelial cell (EC) proliferation and migration are crucial events for angiogenesis and statins are known to enhance these events. However, the molecular mechanism by which statins promote EC proliferation and migration is not fully understood. In this study, we show Akt and its downstream target mammalian target of rapamycin (mTOR) play an important role in pravastatin-induced EC proliferation and migration. We found that pravastatin significantly enhanced the proliferation and migration of rat aortic endothelial cells (rAECs). The addition of pravastatin to rAECs resulted in rapid phosphorylation of Akt and p70 S6 kinase (p70S6K). LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked both Akt and p70S6K phosphorylation, whereas rapamycin, a specific inhibitor of mTOR, suppressed only p70S6K phosphorylation induced by pravastatin. Furthermore, both LY294002 and rapamycin inhibited pravastatin-induced rAEC proliferation and migration. Taken together, our findings indicate that pravastatin activates PI3K/Akt/mTOR /p70S6K signaling in this sequential manner and this pathway contributes to pravastatin-induced rAEC proliferation and migration.
Department of Pharmacology, Osaka City University Medical School, Asahimachi, Osaka, Japan. nakao-t@med.osaka-cu.ac.jp
Takafumi
T
Nakao
Masayuki
M
Shiota
Yasuyoshi
Y
Tatemoto
Yasukatsu
Y
Izumi
Hiroshi
H
Iwao
D000818:Animals; D001011:Aorta / Q000166:cytology; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D002867:Chromones; D004791:Enzyme Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051541:Hepatocyte Nuclear Factor 3-alpha; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017035:Pravastatin; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C499515:FOXO3 protein, rat; C496501:Foxa1 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546845:mTOR protein, rat