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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| Format: | Article |
| Language: | English |
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Elsevier
2017-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050117300645 |
| _version_ | 1811271000779653120 |
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| author | Sarah Hulin-Curtis Helen Williams Kerry S. Wadey Graciela B. Sala-Newby Sarah J. George |
| author_facet | Sarah Hulin-Curtis Helen Williams Kerry S. Wadey Graciela B. Sala-Newby Sarah J. George |
| author_sort | Sarah Hulin-Curtis |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T22:12:12Z |
| format | Article |
| id | doaj.art-c09c64849b9a48fcb6b9185d344effb9 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-12T22:12:12Z |
| publishDate | 2017-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-c09c64849b9a48fcb6b9185d344effb92022-12-22T03:14:41ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012017-06-015C19119910.1016/j.omtm.2017.04.009Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima FormationSarah Hulin-Curtis0Helen Williams1Kerry S. Wadey2Graciela B. Sala-Newby3Sarah J. George4School of Clinical Sciences, University of Bristol, Research Floor Level Seven, Bristol Royal Infirmary, Upper Maudlin St., Bristol BS2 8HW, UKSchool of Clinical Sciences, University of Bristol, Research Floor Level Seven, Bristol Royal Infirmary, Upper Maudlin St., Bristol BS2 8HW, UKSchool of Clinical Sciences, University of Bristol, Research Floor Level Seven, Bristol Royal Infirmary, Upper Maudlin St., Bristol BS2 8HW, UKSchool of Clinical Sciences, University of Bristol, Research Floor Level Seven, Bristol Royal Infirmary, Upper Maudlin St., Bristol BS2 8HW, UKSchool of Clinical Sciences, University of Bristol, Research Floor Level Seven, Bristol Royal Infirmary, Upper Maudlin St., Bristol BS2 8HW, UKApproximately 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.http://www.sciencedirect.com/science/article/pii/S2329050117300645vein graft failureapoptosisvascular smooth muscle cellgene therapycadherinapoptosisintimal thickening |
| spellingShingle | Sarah Hulin-Curtis Helen Williams Kerry S. Wadey Graciela B. Sala-Newby Sarah J. George Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation Molecular Therapy: Methods & Clinical Development vein graft failure apoptosis vascular smooth muscle cell gene therapy cadherin apoptosis intimal thickening |
| 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 | vein graft failure apoptosis vascular smooth muscle cell gene therapy cadherin apoptosis intimal thickening |
| url | http://www.sciencedirect.com/science/article/pii/S2329050117300645 |
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