Abstract 532: The RNA-binding Protein Quaking Critically Regulates Vascular Smooth Muscle Cell Phenotype

Autor: Eric P van der Veer, Ruben G de Bruin, Adriaan O Kraaijeveld, Margreet R de Vries, 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, Ilze Bot, Erna A Peters, Mat Rousch, Merijn Doop, Martin Jan Schalij, Allard C van der Wal, Stehpane Richard, Theo J van Berkel, J. G Pickering, Pieter S Hiemstra, Marie Jose Goumans, Ton J Rabelink, Antoine A de Vries, Paul H Quax, J. W Jukema, Erik A Biessen, Anton Jan van Zonneveld
Rok vydání: 2013
Předmět:
Zdroj: Arteriosclerosis, Thrombosis, and Vascular Biology. 33
ISSN: 1524-4636
1079-5642
DOI: 10.1161/atvb.33.suppl_1.a532
Popis: In response to vascular injury, smooth muscle cells (VSMC) adopt a proliferative, synthetic hypocontractile phenotype. This phenotype switch is deemed instrumental in vascular remodeling in both health and disease. Here, we detail a decisive role for the RNA-binding protein Quaking (QKI) in regulating VSMC plasticity. We identified that the RNA-binding protein Quaking (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 Qk v mice, which have decreased QKI expression. Concordantly, abrogation of QKI attenuated fibroproliferative properties of VSMCs, while potently inducing contractile apparatus protein expression, rendering non-contractile VSMCs with the capacity to contract. We identified that QKI localizes to the spliceosome in proliferative VSMCs, where it interacts with and impacts myocardin (pre)-mRNA metabolism by mediating myocardin exon 2a exclusion. As such, in vitro and in vivo experiments indicate that the modulation of QKI expression directly influences the myocardin_v3 / myocardin_v1 mRNA balance, which could play a role in shifting the Myocardin-induced transcriptional coactivation profile following arterial damage. 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.
Databáze: OpenAIRE
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