ADAR1-Mediated RNA Editing, A Novel Mechanism Controlling Phenotypic Modulation of Vascular Smooth Muscle Cells. Issue 3 (22nd July 2016)

• Record Type: Journal Article
• Authors: Fei, Jia; Cui, Xiao-Bing; Wang, Jia-Ning; Dong, Kun; Chen, Shi-You
• Is Part Of: Circulation research. Volume 119:Issue 3(2016)
• Publication Date: 2016-07-22
• Subjects: ADAR1 -- phenotypic modulation -- RNA editing -- smooth muscle differentiation -- vascular remodeling -- vascular smooth muscle; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.309003
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : 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 α-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 α-actin levels; knockdown of ADAR1 restored SMC myosin heavy chain and smooth muscle α-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 α-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. Abstract : Supplemental Digital Content is available in the text.