title: ADAR1-Mediated RNA Editing, A Novel Mechanism Controlling Phenotypic Modulation of Vascular Smooth Muscle Cells.
abstract: 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.
  
  
  
  To establish RNA editing as a novel mechanism controlling SMC phenotypic modulation.
  
  
  
  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.
  
  
  
  Our results unraveled a novel molecular mechanism, that is, pre-mRNA editing, governing SMC phenotypic modulation.
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens (J.F., X.-B.C., J.-N.W., K.D., S.-Y.C.); and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.).
authors.forename: Jia
authors.initials: J
authors.lastname: Fei
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens (J.F., X.-B.C., J.-N.W., K.D., S.-Y.C.); and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.).
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Cui
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens (J.F., X.-B.C., J.-N.W., K.D., S.-Y.C.); and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.).
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Wang
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens (J.F., X.-B.C., J.-N.W., K.D., S.-Y.C.); and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.).
authors.forename: Kun
authors.initials: K
authors.lastname: Dong
authors.affiliation: From the Department of Physiology and Pharmacology, University of Georgia, Athens (J.F., X.-B.C., J.-N.W., K.D., S.-Y.C.); and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China (J.-N.W., S.-Y.C.). sc229@uga.edu.
authors.forename: Shi-You
authors.initials: SY
authors.lastname: Chen
mesh_terms: D000243:Adenosine Deaminase / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D004311:Double-Blind Method; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D010641:Phenotype; D017393:RNA Editing / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D066253:Vascular Remodeling / Q000502:physiology
chemical_list: C000599465:ADAR1 protein, mouse; D000243:Adenosine Deaminase
keywords: ADAR1; RNA editing; phenotypic modulation; smooth muscle differentiation; vascular remodeling; vascular smooth muscle