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.
School of Clinical Sciences, Research Floor Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, U.K.
Helen
H
Williams
School of Clinical Sciences, Research Floor Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, U.K.
Sadie
S
Slater
School of Clinical Sciences, Research Floor Level 7, Bristol Royal Infirmary, Upper Maudlin St, Bristol BS2 8HW, U.K. s.j.george@bristol.ac.uk.
Sarah Jane
SJ
George
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D015774:Ganciclovir / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018139:Simplexvirus / Q000235:genetics; D051820:TCF Transcription Factors / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
D000998:Antiviral Agents; D051820:TCF Transcription Factors; D051176:beta Catenin; D013937:Thymidine Kinase; D015774:Ganciclovir
Wnt; gene therapy; neointima formation; restenosis; β-catenin