Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular Smooth Muscle Cell Phenotype

Eric P. van der Veer*, Ruben G. de Bruin, Adriaan O. Kraaijeveld, Margreet R. de Vries, Ilze Bot, Tonio Pera, Filip M. Segers, Stella Trompet, Janine M. van Gils, Marko K. Roeten, Cora M. Beckers, Peter J. van Santbrink, Anique Janssen, Coen van Solingen, Jim Swildens, Hetty C. de Boer, Erna A. Peters, Roel Bijkerk, Mat Rousch, Merijn DoopJohan Kuiper, Martin Jan Schalij, Allard C. van der Wal, Stephane Richard, Theo J. C. van Berkel, J. Geoffrey Pickering, Pieter S. Hiemstra, Marie-Jose Goumans, Ton J. Rabelink, Antoine A. F. de Vries, Paul H. A. Quax, J. Wouter Jukema, Erik A. L. Biessen, Anton Jan van Zonneveld

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Rationale: 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. Methods and 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.
Original languageEnglish
Pages (from-to)1065-1075
JournalCirculation Research
Issue number9
Publication statusPublished - 12 Oct 2013


  • alternative splicing
  • differentiation
  • myocardin
  • Qk
  • restenosis
  • RNA-binding protein Quaking
  • vascular injury
  • vascular smooth muscle cells

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