| First Author | Chen Q | Year | 2015 |
| Journal | J Mol Cell Cardiol | Volume | 89 |
| Issue | Pt A | Pages | 75-86 |
| PubMed ID | 26493107 | Mgi Jnum | J:250656 |
| Mgi Id | MGI:6102026 | Doi | 10.1016/j.yjmcc.2015.10.017 |
| Citation | Chen Q, et al. (2015) miRNA-34a reduces neointima formation through inhibiting smooth muscle cell proliferation and migration. J Mol Cell Cardiol 89(Pt A):75-86 |
| abstractText | AIMS: We have recently reported that microRNA-34a (miR-34a) regulates vascular smooth muscle cell (VSMC) differentiation from stem cells in vitro and in vivo. However, little is known about the functional involvements of miR-34a in VSMC functions and vessel injury-induced neointima formation. In the current study, we aimed to establish the causal role of miR-34a and its target genes in VSMC proliferation, migration and neointima lesion formation. METHODS AND RESULTS: Various pathological stimuli regulate miR-34a expression in VSMCs through a transcriptional mechanism, and the P53 binding site is required for miR-34a gene regulation by these stimuli. miR-34a over-expression in serum-starved VSMCs significantly inhibited VSMC proliferation and migration, while knockdown of miR-34a dramatically promoted VSMC proliferation and migration, respectively. Notch homolog 1 (Notch1), a well-reported regulator in VSMC functions and arterial remodeling, was predicted as one of the top targets of miR-34a by using several computational miRNA target prediction tools, and was negatively regulated by miR-34a in VSMCs. Luciferase assay showed miR-34a substantially repressed wild type Notch1-3''-UTR-luciferase activity in VSMCs, but not mutant Notch1-3''-UTR-luciferease reporter, confirming the Notch1 is the functional target of miR-34a in VSMCs. Data from co-transfection experiments also revealed that miR-34a inhibited VSMC proliferation and migration through modulating Notch gene expression levels. Importantly, the expression level of miR-34a was significantly down-regulated in injured arteries, and miR-34a perivascular over-expression significantly reduced Notch1 expression levels, decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries. CONCLUSION: Our data have demonstrated that miR-34a is an important regulator in VSMC functions and neointima hyperplasia, suggesting its potential therapeutic application for vascular diseases. |
