| First Author | Volkmann I | Year | 2013 |
| Journal | Circ Res | Volume | 113 |
| Issue | 8 | Pages | 997-1003 |
| PubMed ID | 23960241 | Mgi Jnum | J:213464 |
| Mgi Id | MGI:5584376 | Doi | 10.1161/CIRCRESAHA.113.301702 |
| Citation | Volkmann I, et al. (2013) MicroRNA-mediated epigenetic silencing of sirtuin1 contributes to impaired angiogenic responses. Circ Res 113(8):997-1003 |
| abstractText | RATIONALE: Transforming growth factor (TGF)-beta was linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses. Its effect on microRNAs and downstream targets in this context is not known. OBJECTIVE: To study the role of microRNAs in TGF-beta-mediated angiogenic activity. METHODS AND RESULTS: MicroRNA profiling after TGF-beta treatment of endothelial cells identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. Supplementation of miR-30a-3p restored function in TGF-beta-treated endothelial cells. We identified the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p. Viral overexpression of MeCP2 mimicked the effects of TGF-beta, suggesting that derepression of MeCP2 after TGF-beta treatment may be responsible for impaired angiogenic responses. Silencing of MeCP2 rescued detrimental TGF-beta effects on endothelial cells. Microarray transcriptome analysis of MeCP2-overexpressing endothelial cells identified several deregulated genes important for endothelial cell function including sirtuin1 (Sirt1). In vivo experiments using endothelial cell-specific MeCP2 null or Sirt1 transgenic mice confirmed the involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells. Additional experiments identified that MeCP2 inhibited endothelial angiogenic characteristics partly by epigenetic silencing of Sirt1. CONCLUSIONS: TGF-beta impairs endothelial angiogenic responses partly by downregulating miR-30a-3p and subsequent derepression of MeCP2-mediated epigenetic silencing of Sirt1. |
