Simvastatin stimulates vascular endothelial growth factor production by hypoxia-inducible factor-1alpha upregulation in endothelial cells.
OBJECTIVE
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor and plays an important pathophysiological role in the maintenance of tissue structure as well as regeneration after ischemic injury. Three-hydroxy-3methylglutaryl-CoA reductase inhibitors reduce vascular inflammation and induce angiogenesis. This study examined whether simvastatin stimulates VEGF expression in endothelial cells as well as the nature of its underlying mechanism.


RESULTS
Simvastatin induced mRNA expression and protein secretion of VEGF in endothelial cells that were reversed by pretreatment with mevalonate and geranylgeranylpyrophosphate but not by farnesylpyrophosphate. Adenovirus-mediated expression of the dominant-negative mutant of RhoA induced VEGF mRNA and protein. Simvastatin increased hypoxia-inducible factor-1alpha (HIF-1alpha) protein level without changing its mRNA expression. Inhibition of RhoA had similar effects to simvastatin on VEGF expression. Inhibition of RhoA caused the translocation of HIF-1alpha to the nuclear fraction. Depletion of HIF-1alpha by RNA interference blocked simvastatin-induced VEGF mRNA expression.


CONCLUSIONS
Simvastatin stimulates VEGF expression by RhoA downregulation and HIF-1alpha upregulation in endothelial cells. These data indicate a novel role for RhoA as a negative regulator of HIF-1alpha.
Nishimoto-Hazuku
Ai
A
Department of Cardiovascular and Renal Medicine, Saga University Faculty of Medicine, Saga, Japan.
Hirase
Tetsuaki
T
Ide
Noriko
N
Ikeda
Yuji
Y
Node
Koichi
K
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D019821:Simvastatin; D020742:rhoA GTP-Binding Protein