Suppression of neointima formation by targeting β-catenin/TCF pathway.
Coronary artery disease is treated by vein grafting and stent implantation. Late vein graft failure and restenosis of stented arteries reduce the success rates of these approaches and are caused by neointima formation. We have previously shown that Wnt proteins are up-regulated during intimal thickening, and have speculated that these lead to activation of downstream genes with β-catenin/T-cell factor (TCF)-responsive promoters. In the present study, we aimed to provide evidence that β-catenin/TCF signalling promotes neointima formation and assess whether targeting this pathway has potential for reducing neointima formation. We utilized a gene therapy approach selectively targeting cells in which the β-catenin/TCF pathway is activated by using a recombinant adenovirus Ad-TOPTK, which carries a herpes simplex virus thymidine kinase (HSV-TK) gene under the control of a β-catenin/TCF-response promoter. Cells with activated β-catenin will therefore be selectively killed. Ad-TOPTK and ganciclovir (GCV) treatment significantly suppressed the growth of the neointima in a murine model of left carotid artery ligation. In summary, we demonstrated that Wnt/β-catenin/TCF signalling promotes neointima formation, by showing that the selective death of cells with activated β-catenin suppressed neointima formation. This highlights the therapeutic potential for reducing late vein graft failure and in-stent restenosis by targeting β-catenin/TCF signalling.
['Williams|Helen|H|', 'Slater|Sadie|S|', 'George|Sarah Jane|SJ|']
D000256:Adenoviridae D000818:Animals D000998:Antiviral Agents D002478:Cells, Cultured D015774:Ganciclovir D005822:Genetic Vectors D006801:Humans D051379:Mice D008810:Mice, Inbred C57BL D058426:Neointima D011401:Promoter Regions, Genetic D015398:Signal Transduction D018139:Simplexvirus D051820:TCF Transcription Factors D013937:Thymidine Kinase D015854:Up-Regulation D060449:Wnt Signaling Pathway D051176:beta Catenin
neointima formation β-catenin restenosis Wnt gene therapy