title: Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype.
abstract: BACKGROUND
  RNA-binding proteins are critical post-transcriptional regulators of RNA and can influence pre-mRNA splicing, RNA localization, and stability. The RNA-binding protein Quaking (QKI) is essential for embryonic blood vessel development. However, the role of QKI in the adult vasculature, and in particular in vascular smooth muscle cells (VSMCs), is currently unknown.
  
  
  OBJECTIVE
  We sought to determine the role of QKI in regulating adult VSMC function and plasticity.
  
  
  RESULTS
  We identified that QKI is highly expressed by neointimal VSMCs of human coronary restenotic lesions, but not in healthy vessels. In a mouse model of vascular injury, we observed reduced neointima hyperplasia in Quaking viable mice, which have decreased QKI expression. Concordantly, abrogation of QKI attenuated fibroproliferative properties of VSMCs, while potently inducing contractile apparatus protein expression, rendering noncontractile VSMCs with the capacity to contract. We identified that QKI localizes to the spliceosome, where it interacts with the myocardin pre-mRNA and regulates the splicing of alternative exon 2a. This post-transcriptional event impacts the Myocd_v3/Myocd_v1 mRNA balance and can be modulated by mutating the quaking response element in exon 2a of myocardin. Furthermore, we identified that arterial damage triggers myocardin alternative splicing and is tightly coupled with changes in the expression levels of distinct QKI isoforms.
  
  
  CONCLUSIONS
  We propose that QKI is a central regulator of VSMC phenotypic plasticity and that intervention in QKI activity can ameliorate pathogenic, fibroproliferative responses to vascular injury.
authors: From the Einthoven Laboratory of Experimental Vascular Medicine.
authors: Eric P
authors: EP
authors: van der Veer
authors: Ruben G
authors: RG
authors: de Bruin
authors: Adriaan O
authors: AO
authors: Kraaijeveld
authors: Margreet R
authors: MR
authors: de Vries
authors: Ilze
authors: I
authors: Bot
authors: Tonio
authors: T
authors: Pera
authors: Filip M
authors: FM
authors: Segers
authors: Stella
authors: S
authors: Trompet
authors: Janine M
authors: JM
authors: van Gils
authors: Marko K
authors: MK
authors: Roeten
authors: Cora M
authors: CM
authors: Beckers
authors: Peter J
authors: PJ
authors: van Santbrink
authors: Anique
authors: A
authors: Janssen
authors: Coen
authors: C
authors: van Solingen
authors: Jim
authors: J
authors: Swildens
authors: Hetty C
authors: HC
authors: de Boer
authors: Erna A
authors: EA
authors: Peters
authors: Roel
authors: R
authors: Bijkerk
authors: Mat
authors: M
authors: Rousch
authors: Merijn
authors: M
authors: Doop
authors: Johan
authors: J
authors: Kuiper
authors: Martin Jan
authors: MJ
authors: Schalij
authors: Allard C
authors: AC
authors: van der Wal
authors: Stéphane
authors: S
authors: Richard
authors: Theo J C
authors: TJ
authors: van Berkel
authors: J Geoffrey
authors: JG
authors: Pickering
authors: Pieter S
authors: PS
authors: Hiemstra
authors: Marie Jose
authors: MJ
authors: Goumans
authors: Ton J
authors: TJ
authors: Rabelink
authors: Antoine A F
authors: AA
authors: de Vries
authors: Paul H A
authors: PH
authors: Quax
authors: J Wouter
authors: JW
authors: Jukema
authors: Erik A L
authors: EA
authors: Biessen
authors: Anton Jan
authors: AJ
authors: van Zonneveld
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D023903:Coronary Restenosis / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008821:Mice, Quaking; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000099251:Myocardin
chemical_list: D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D000099251:Myocardin; C490832:QKI protein, human; C098217:Qk protein, mouse
keywords: Qk; RNA-binding protein Quaking; alternative splicing; differentiation; myocardin; restenosis; vascular injury; vascular smooth muscle cells