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ADAR1-Mediated RNA Editing, A Novel Mechanism Controlling Phenotypic Modulation
of Vascular Smooth Muscle Cells
#MMPMID27199464
Fei J
; Cui XB
; Wang JN
; Dong K
; Chen SY
Circ Res
2016[Jul]; 119
(3
): 463-9
PMID27199464
show ga
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 ?-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 ?-actin levels; knockdown of ADAR1
restored SMC myosin heavy chain and smooth muscle ?-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 ?-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.
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