Abstract 532: The RNA-binding Protein Quaking Critically Regulates Vascular Smooth Muscle Cell Phenotype
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 Qkv 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.
- © 2013 by American Heart Association, Inc.