Abstract
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.
Highlights
Migration and proliferation of vascular smooth muscle cells (VSMCs) to form a neointima occur in pathologies such as restenosis after angioplasty and vein grafting
Selective killing of VSMC with β-catenin signalling In order to test the hypothesis that VSMCs can be selectively killed by targeting β-catenin/T-cell factor (TCF) pathway with a responsive promoter, VSMCs were infected with Ad-TOPTK with or without Ad-β-catenin and cultured in the presence or absence of GCV
VSMCs with increased levels of active β-catenin are selectively killed by Ad-TOPTK Human saphenous vein VSMCs were infected with 1000 pfu/cell Ad-thymidine kinase (Ad-thymidine kinase (TK)), Ad-β-gal, Ad-TOPTK with or without 300 pfu/cell Ad-β-gal or Ad-β-catenin and cultured in the presence or absence of GCV
Summary
Migration and proliferation of vascular smooth muscle cells (VSMCs) to form a neointima occur in pathologies such as restenosis after angioplasty and vein grafting. Our recent work has shown the involvement of the Wnt/β-catenin pathway in both migration [1,2] and proliferation [3]. This has been confirmed by work in other groups [4,5,6]. It has never been shown directly that β-catenin/T-cell factor (TCF) signalling is directly required for neointima formation in vivo. We aimed to show that β-catenin/TCF signalling is required for neointima formation and to examine whether using a suicide gene approach, similar to that previously utilized by Kwong et al [7] in a mouse model of colon cancer, could retard neointima formation following complete carotid artery ligation in mice. We have utilized an adenoviral vector in which expression of the herpes simplex virus thymidine kinase (HSV-TK) gene is driven by a novel β-catenin/TCF-
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