Cited 61 times since 2013 (5.7 per year) source: EuropePMC Circulation research, Volume 113, Issue 9, 20 3 2013, Pages 1065-1075 Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype. van der Veer EP, de Bruin RG, Kraaijeveld AO, de Vries MR, Bot I, Pera T, Segers FM, Trompet S, van Gils JM, Roeten MK, Beckers CM, van Santbrink PJ, Janssen A, van Solingen C, Swildens J, de Boer HC, Peters EA, Bijkerk R, Rousch M, Doop M, Kuiper J, Schalij MJ, van der Wal AC, Richard S, van Berkel TJ, Pickering JG, Hiemstra PS, Goumans MJ, Rabelink TJ, de Vries AA, Quax PH, Jukema JW, Biessen EA, van Zonneveld AJ
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.
