ADAR1-Mediated RNA Editing, A Novel Mechanism Controlling Phenotypic Modulation of Vascular Smooth Muscle Cells
Rationale: Vascular smooth muscle (SMC) phenotypic modulation is characterized by the down-regulation of SMC contractile genes. Platelet-derived growth factor-BB (PDGF-BB), a well-known stimulator of SMC phenotypic modulation, down-regulates 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 (SMMHC) and α-actin (α-SMA) were accumulated while their mature mRNAs were down-regulated 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 SMMHC and α-SMA levels; knockdown of ADAR1 restored SMMHC and α-SMA 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 SMMHC and α-SMA 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, i.e., pre-mRNA editing, governing SMC phenotypic modulation.
- Phenotypic modulation
- RNA editing
- vascular smooth muscle
- vascular remodeling
- smooth muscle differentiation
- Received April 28, 2016.
- Revision received May 12, 2016.
- Accepted May 19, 2016.