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Inhibition of NFκB activation using cis-element ‘decoy’ of NFκB binding site reduces neointimal formation in porcine balloon-injured coronary artery model

Abstract

Application of DNA technology to regulate the transcription of disease-related genes has important therapeutic potential. The transcription factor NFκB plays a pivotal role in the transactivation of inflammatory and adhesion molecule genes, leading to vascular lesion formation. Double-stranded DNA with high affinity for NFκB may be introduced as ‘decoy’ cis elements to bind NFκB and block the activation of genes mediating inflammation, resulting in effective drugs for treating intimal hyperplasia. In this study, we tested the feasibility of NFκB decoy therapy to treat neointimal formation in a porcine coronary artery balloon injury model as a pre-clinical study.

An angioplasty catheter was introduced into the left anterior descending coronary artery of the pig to cause vascular injury. First, we tested the feasibility of transfection of FITC-labeled NFκB decoy ODN using a hydrogel balloon catheter. Fluorescence due to NFκB decoy ODN could be detected throughout the medial layer. Therefore, we transfected NFκB decoy ODN into the balloon-injured LAD using a hydrogel catheter. Histological evaluation demonstrated that the neointimal area in the balloon-injured artery was significantly reduced by NFκB decoy ODN as compared to scrambled decoy ODN at 1 week after single transfection, accompanied by a significant reduction in PCNA-positive stained cells (P<0.01). Interestingly, the reduction of ICAM-positive staining was observed, accompanied by the inhibition of migration of macrophages. Of importance, intravascular ultrasound (IVUS) confirmed that neointimal area in the balloon-injured artery was significantly reduced by NFκB decoy ODN at 4 weeks after transfection (P<0.01). Interestingly, the inhibition of neointimal area was only limited to the lesion transfected with NFκB decoy ODN, while other lesions without NFκB decoy ODN demonstrated a marked increase in neointimal formation.

Here, we report the successful in vivo transfer of NFκB decoy ODN using a hydrogel catheter to inhibit vascular lesion formation in balloon-injured porcine coronary artery.

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Acknowledgements

This work was partially supported by a Grant-in-Aid from the Ministry of Public Health and Welfare, a Grant-in-Aid for the Development of Innovative Technology, a Grant-in-Aid from Japan Promotion of Science, and Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government.

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Yamasaki, K., Asai, T., Shimizu, M. et al. Inhibition of NFκB activation using cis-element ‘decoy’ of NFκB binding site reduces neointimal formation in porcine balloon-injured coronary artery model. Gene Ther 10, 356–364 (2003). https://doi.org/10.1038/sj.gt.3301875

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