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

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 dom...

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Autores principales: Hulin-Curtis, Sarah, Williams, Helen, Wadey, Kerry S., Sala-Newby, Graciela B., George, Sarah J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430493/
https://www.ncbi.nlm.nih.gov/pubmed/28540322
http://dx.doi.org/10.1016/j.omtm.2017.04.009
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author Hulin-Curtis, Sarah
Williams, Helen
Wadey, Kerry S.
Sala-Newby, Graciela B.
George, Sarah J.
author_facet Hulin-Curtis, Sarah
Williams, Helen
Wadey, Kerry S.
Sala-Newby, Graciela B.
George, Sarah J.
author_sort Hulin-Curtis, Sarah
collection PubMed
description 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.
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spelling pubmed-54304932017-05-24 Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation Hulin-Curtis, Sarah Williams, Helen Wadey, Kerry S. Sala-Newby, Graciela B. George, Sarah J. Mol Ther Methods Clin Dev Original Article 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. American Society of Gene & Cell Therapy 2017-05-04 /pmc/articles/PMC5430493/ /pubmed/28540322 http://dx.doi.org/10.1016/j.omtm.2017.04.009 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Hulin-Curtis, Sarah
Williams, Helen
Wadey, Kerry S.
Sala-Newby, Graciela B.
George, Sarah J.
Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation
title Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation
title_full Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation
title_fullStr Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation
title_full_unstemmed Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation
title_short Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation
title_sort targeting wnt/β-catenin activated cells with dominant-negative n-cadherin to reduce neointima formation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430493/
https://www.ncbi.nlm.nih.gov/pubmed/28540322
http://dx.doi.org/10.1016/j.omtm.2017.04.009
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