Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation

Hulin-Curtis, Sarah L ORCID: 0000-0003-0889-964X, Williams, Helen, Wadey, Kerry S, Sala-Newby, Graciela B and George, Sarah J (2017) Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation. Molecular Therapy - Methods & Clinical Development, 5. pp. 191-199. doi:10.1016/j.omtm.2017.04.009

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Text 14145 Hulin-Curtis, Williams, Wadey, Sala-Newby, George (2017) Targeting Wnt-B-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation.pdf - Published Version Available under License Creative Commons Attribution 4.0. Download (1MB) | Preview

Abstract

Approximately 50% of coronary artery bypass grafts using the autologous saphenous vein fail within 10 years due to intimal thickening. This study examined whether a gene therapy approach that selectively kills Wnt/β-catenin/T cell factor (TCF) activated vascular smooth muscle cells (VSMCs) using dominant-negative N-cadherin (dn-N-cadherin) reduced intimal thickening. Cultured human VSMCs infected with an adenovirus (Ad) encoding dn-N-cadherin via the TCF promoter (Ad-TOP-dn-N-cadherin) specifically expressed dn-N-cadherin in response to activation of the Wnt/β-catenin/TCF pathway. Infection with Ad-TOP-dn-N-cadherin significantly increased VSMC apoptosis (3 ± 0.2% versus 9 ± 0.7%; p < 0.05, n = 6) and significantly inhibited VSMC migration by 83 ± 15% (p < 0.05, n = 6), but did not affect VSMC proliferation (p > 0.05, n = 5). In an ex vivo human saphenous vein organ culture model, luminal delivery of Ad-TOP-dn-N-cadherin significantly increased VSMC apoptosis after 7 days of culture (4 ± 1.4% versus 9 ± 1.6%; p < 0.01, n = 6) and suppressed intimal thickening by 75 ± 7% (p < 0.05, n = 5), without a detrimental effect on endothelial cell coverage. In vivo, Ad-TOP-dn-N-cadherin significantly reduced intimal thickening at day 21 (n = 10) in comparison to the Ad-β-galactosidase (Ad-β-gal) control virus (n = 12, p < 0.05) in the mouse carotid artery ligation model. In summary, we have developed a novel approach to selectively reduce intimal thickening, which may be beneficial in reducing late vein graft failure.

Item Type:	Article
Article Type:	Article
Uncontrolled Keywords:	Vein graft failure; Apoptosis; Vascular smooth muscle cell; Gene therapy; Cadherin; Apoptosis; Intimal thickening
Subjects:	R Medicine > R Medicine (General)
Divisions:	Schools and Research Institutes > School of Education and Science
Research Priority Areas:	Health, Life Sciences, Sport and Wellbeing
Depositing User:	Sarah Curtis
Date Deposited:	17 Jun 2024 09:13
Last Modified:	17 Jun 2024 09:15
URI:	https://eprints.glos.ac.uk/id/eprint/14145

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