論文 - 詳細
| RRC ID | 41778 |
|---|---|
| 著者 | Maeda T, Kawane T, Horiuchi N. |
| タイトル | Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation. |
| ジャーナル | 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. |
| 巻・号 | 144(2) |
| ページ | 681-92 |
| 公開日 | 2003-2-1 |
| 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 | 3.934 |
| 引用数 | 164 |
| WOS 分野 | ENDOCRINOLOGY & METABOLISM |
| オルトメトリクス指標 |
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | ST2(RCB0224) |