RRC ID 41778
Author Maeda T, Kawane T, Horiuchi N.
Title Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation.
Journal Endocrinology
Abstract Statins such as simvastatin are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that inhibit cholesterol synthesis. We presently investigated statin effects on vascular endothelial growth factor (VEGF) expression in osteoblastic cells. Hydrophobic statins including simvastatin, atorvastatin, and cerivastatin-but not a hydrophilic statin, pravastatin-markedly increased VEGF mRNA abundance in nontransformed osteoblastic cells (MC3T3-E1). Simvastatin (10(-6) M) time-dependently augmented VEGF mRNA expression in MC3T3-E1 cells, mouse stromal cells (ST2), and rat osteosarcoma cells (UMR-106). According to heterogeneous nuclear RNA and Northern analyses, 10(-6) M simvastatin stimulated gene expression for VEGF in MC3T3-E1 cells without altering mRNA stability. Transcriptional activation of a VEGF promoter-luciferase construct (-1128 to +827), significantly increased by simvastatin administration. As demonstrated by gel mobility shift assay, simvastatin markedly enhanced the binding of hypoxia-responsive element-protein complexes. These results indicate that the stimulation of the VEGF gene by simvastatin in MC3T3-E1 cells is transcriptional in nature. VEGF secretion into medium was increased in MC3T3-E1 by 10(-6) M simvastatin. Pretreating MC3T3-E1 cells with mevalonate or geranylgeranyl pyrophosphate, a mevalonate metabolite, abolished simvastatin-induced VEGF mRNA expression; manumycin A, a protein prenylation inhibitor, mimicked statin effects on VEGF expression. The effect of simvastatin was blocked by pretreatment with wortmannin and LY294002, specific phosphatidylinositide-3 kinase inhibitors. Simvastatin enhanced mineralized nodule formation in culture, whereas coincubation with mevalonate, geranylgeranyl pyrophosphate, LY294002, or VEGF receptor 2 inhibitor (SU1498) abrogated statin-induced mineralization. Thus, statins stimulate VEGF expression in osteoblasts via reduced protein prenylation and the phosphatidylinositide-3 kinase pathway, promoting osteoblastic differentiation.
Volume 144(2)
Pages 681-92
Published 2003-2
DOI 10.1210/en.2002-220682
PMID 12538631
MeSH Animals Bone Morphogenetic Protein 2 Bone Morphogenetic Proteins / genetics Calcification, Physiologic / drug effects Cell Line Cholesterol / metabolism Endothelial Growth Factors / genetics* Endothelial Growth Factors / metabolism Gene Expression / drug effects Hypolipidemic Agents / pharmacology* Intercellular Signaling Peptides and Proteins / genetics* Intercellular Signaling Peptides and Proteins / metabolism Lymphokines / genetics* Lymphokines / metabolism Mice Molecular Sequence Data Osteoblasts / cytology Osteoblasts / metabolism Osteoblasts / physiology* Protein Prenylation / drug effects RNA, Messenger / analysis Simvastatin / pharmacology* Skull / cytology Transcriptional Activation / drug effects Transforming Growth Factor beta* Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
IF 3.961
Times Cited 121
Human and Animal Cells