Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular Smooth Muscle Cell Phenotype
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| Title: | Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular Smooth Muscle Cell Phenotype |
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| Authors: | Veer, E.P. van der, Bruin, R.G. de, Kraaijeveld, A.O., Vries, M.R. de, Bot, I., Pera, T., Segers, F.M., Trompet, S., Gils, J.M. van, Roeten, M.K., Beckers, C.M., Santbrink, P.J. van, Janssen, A., Solingen, C. van, Swildens, J., Boer, H.C. de, Peters, E.A., Bijkerk, R., Rousch, M., Doop, M., Kuiper, J., Schalij, M.J., Wal, A.C. van der, Richard, S., Berkel, T.J.C. van, Pickering, J.G., Hiemstra, P.S., Goumans, M.J., Rabelink, T.J., Vries, A.A.F. de, Quax, P.H.A., Jukema, J.W., Biessen, E.A.L., Zonneveld, A.J. van |
| Source: | Circulation Research. 113:1065-1075 |
| Publisher Information: | Ovid Technologies (Wolters Kluwer Health), 2013. |
| Publication Year: | 2013 |
| Subject Terms: | 0301 basic medicine, Carotid Artery, Common, Qk, Myocytes, Smooth Muscle, RNA-binding protein Quaking, Muscle, Smooth, Vascular, Coronary Restenosis, alternative splicing, restenosis, Mice, 03 medical and health sciences, Cell Movement, vascular smooth muscle cells, Animals, Humans, Mice, Quaking, myocardin, vascular injury, Cell Proliferation, 0303 health sciences, Hyperplasia, differentiation, Coronary Vessels, Extracellular Matrix, Mice, Inbred C57BL, Alternative Splicing, Disease Models, Animal, HEK293 Cells, Gene Expression Regulation, Female, Carotid Artery Injuries |
| Description: | 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. |
| Document Type: | Article |
| Language: | English |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.113.301302 |
| Access URL: | https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.113.301302 https://pubmed.ncbi.nlm.nih.gov/23963726 https://www.ahajournals.org/doi/full/10.1161/circresaha.113.301302 https://pubmed.ncbi.nlm.nih.gov/23963726/ https://cris.maastrichtuniversity.nl/en/publications/quaking-an-rna-binding-protein-is-a-critical-regulator-of-vascula http://circres.ahajournals.org/lookup/pmid?view=long&pmid=23963726 https://europepmc.org/article/MED/23963726 https://www.ncbi.nlm.nih.gov/pubmed/23963726 https://hdl.handle.net/1887/102815 https://pure.amsterdamumc.nl/en/publications/198edc8f-0ae5-4c15-9374-336047d046b3 https://doi.org/10.1161/CIRCRESAHA.113.301302 |
| Accession Number: | edsair.doi.dedup.....daed862a40abcd5c242104df7f42580f |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | 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. |
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| ISSN: | 15244571 00097330 |
| DOI: | 10.1161/circresaha.113.301302 |