Jia Fei1, Xiao-Bing Cui1, Jia-Ning Wang1, Kun Dong1, Shi-You Chen2. 1. 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.). 2. 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.
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.
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.
Authors: C E Hart; L W Kraiss; S Vergel; D Gilbertson; R Kenagy; T Kirkman; D L Crandall; S Tickle; H Finney; G Yarranton; A W Clowes Journal: Circulation Date: 1999-02-02 Impact factor: 29.690
Authors: T Christen; M L Bochaton-Piallat; P Neuville; S Rensen; M Redard; G van Eys; G Gabbiani Journal: Circ Res Date: 1999-07-09 Impact factor: 17.367
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