| First Author | Fei J | Year | 2016 |
| Journal | Circ Res | Volume | 119 |
| Issue | 3 | Pages | 463-9 |
| PubMed ID | 27199464 | Mgi Jnum | J:250945 |
| Mgi Id | MGI:6100798 | Doi | 10.1161/CIRCRESAHA.116.309003 |
| Citation | Fei J, et al. (2016) ADAR1-Mediated RNA Editing, A Novel Mechanism Controlling Phenotypic Modulation of Vascular Smooth Muscle Cells. Circ Res 119(3):463-9 |
| abstractText | RATIONALE: Vascular smooth muscle cell (SMC) phenotypic modulation is characterized by the downregulation of SMC contractile genes. Platelet-derived growth factor-BB, a well-known stimulator of SMC phenotypic modulation, downregulates SMC genes via posttranscriptional regulation. The underlying mechanisms, however, remain largely unknown. OBJECTIVE: To establish RNA editing as a novel mechanism controlling SMC phenotypic modulation. METHODS AND RESULTS: Precursor mRNAs (pre-mRNA) of SMC myosin heavy chain and smooth muscle alpha-actin were accumulated while their mature mRNAs were downregulated during SMC phenotypic modulation, suggesting an abnormal splicing of the pre-mRNAs. The abnormal splicing resulted from SMC marker pre-mRNA editing that was facilitated by adenosine deaminase acting on RNA 1 (ADAR1), an enzyme converting adenosines to inosines (A-->I editing) in RNA sequences. ADAR1 expression inversely correlated with SMC myosin heavy chain and smooth muscle alpha-actin levels; knockdown of ADAR1 restored SMC myosin heavy chain and smooth muscle alpha-actin expression in phenotypically modulated SMC, and editase domain mutation diminished the ADAR1-mediated abnormal splicing of SMC marker pre-mRNAs. Moreover, the abnormal splicing/editing of SMC myosin heavy chain and smooth muscle alpha-actin pre-mRNAs occurred during injury-induced vascular remodeling. Importantly, heterozygous knockout of ADAR1 dramatically inhibited injury-induced neointima formation and restored SMC marker expression, demonstrating a critical role of ADAR1 in SMC phenotypic modulation and vascular remodeling in vivo. CONCLUSIONS: Our results unraveled a novel molecular mechanism, that is, pre-mRNA editing, governing SMC phenotypic modulation. |
