Protein kinase CK2 inhibition suppresses neointima formation via a proline-rich homeodomain-dependent mechanism

Wadey, K.S.; Brown, Bethan; Sala-Newby, G.B.; Jayaraman, P.-S.; Gaston, K.; George, S.J.

Abstract

Neointimal hyperplasia is a product of VSMC replication and consequent accumulation within the blood vessel wall. In this study, we determined whether inhibition of protein kinase CK2 and the resultant stabilisation of proline-rich homeodomain (PRH) could suppress VSMC proliferation. Both silencing and pharmacological inhibition of CK2 with K66 antagonised replication of isolated VSMCs. SiRNA-induced knockdown as well as ectopic overexpression of proline-rich homeodomain indicated that PRH disrupts cell cycle progression. Mutation of CK2 phosphorylation sites Ser163 and Ser177 within the PRH homeodomain enabled prolonged cell cycle arrest by PRH. Concomitant knockdown of PRH and inhibition of CK2 with K66 indicated that the anti-proliferative action of K66 required the presence of PRH. Both K66 and adenovirus-mediated gene transfer of S163C:S177C PRH impaired neointima formation in human saphenous vein organ cultures. Importantly, neither intervention had notable effects on cell cycle progression, cell survival or migration in cultured endothelial cells.

Citation

Wadey, K., Brown, B., Sala-Newby, G., Jayaraman, P.-S., Gaston, K., & George, S. (2017). Protein kinase CK2 inhibition suppresses neointima formation via a proline-rich homeodomain-dependent mechanism. Vascular Pharmacology, 99, 34--44. https://doi.org/10.1016/j.vph.2017.09.004

• Journal Article Type: Article
• Acceptance Date: Sep 14, 2017
• Online Publication Date: Sep 18, 2017
• Publication Date: Dec 1, 2017
• Deposit Date: Aug 24, 2018
• Publicly Available Date: Aug 24, 2018
• Journal: Vascular Pharmacology
• Print ISSN: 1537-1891
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 99
• Pages: 34--44
• DOI: https://doi.org/10.1016/j.vph.2017.09.004
• Keywords: Atherosclerosis, CK2, In-stent restenosis, PRH, Vascular smooth muscle, Vein graft
• Public URL: https://nottingham-repository.worktribe.com/output/1037551
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1537189117300800
• Contract Date: Aug 24, 2018