Interferon‐induced protein 35 inhibits endothelial cell proliferation, migration and re‐endothelialization of injured arteries by inhibiting the nuclear factor‐kappa B pathway

• Published in: Acta Physiologica Vol. 223; no. 3; pp. e13037 - n/a
• Main Authors: Jian, D., Wang, W., Zhou, X., Jia, Z., Wang, J., Yang, M., Zhao, W., Jiang, Z., Hu, X., Zhu, J.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2018
• Subjects: Adenoviruses; Arteries; Arteriosclerosis; Carotid artery; Cell growth; Cell migration; Cell proliferation; Clonal deletion; endothelial cell; Endothelial cells; Hyperplasia; Inflammation; Interferon; interferon‐induced protein 35; Kinases; nuclear factor‐kappa B; Proteins; re‐endothelialization; Rodents; siRNA; Umbilical vein; nuclear factor-kappa B; interferon-induced protein 35; endothelial cell; re-endothelialization
• ISSN: 1748-1708; 1748-1716
• DOI: 10.1111/apha.13037

Aim Endothelial recovery, or re‐endothelialization, plays an important role in intimal hyperplasia and atherosclerosis after endothelial injury. Studying the mechanisms of re‐endothelialization and strategies to promote efficient endothelial recovery are still needed. Interferon‐induced protein 35 (IFI35) is an IFN‐γ‐induced protein that plays important roles in the antivirus‐related immune‐inflammatory response. In this study, we tested whether overexpression IFI35 affects the proliferation and migration of endothelial cells (ECs) and re‐endothelialization. Methods Wire injury of the carotid artery was induced in C57BL/6 mice, which was followed by IFI35 or null adenovirus transduction. Evans blue staining and HE staining were performed to evaluate the re‐endothelialization rate and neointima formation. In vitro studies, primary human umbilical vein endothelial cells (HUVECs) were transfected with Ad‐IFI35 or siRNA‐IFI35 to evaluate its potential roles in cell proliferation and migration. Furthermore, the potential mechanism relating inhibition of NF‐κB/p65 pathway was elaborated by luciferase assay and IFI35 domain deletion assay. Results In IFI35 adenovirus‐transduced mice, the re‐endothelialization rates at days 3, 7 were significantly reduced compared to those in null adenovirus‐transduced mice (5% and 35%, vs 20% and 50%, respectively). Meanwhile, subsequent neointimal hyperplasia was obviously increased in IFI35 adenovirus‐transduced mice. In vitro studies further indicated that IFI35 inhibits both EC proliferation and migration by inhibiting the NF‐κB/p65 pathway. Subsequent studies demonstrated that IFI35 functionally interacted with Nmi through its NID1 domain and that knock‐down of Nmi significantly mitigated the inhibitory effect of IFI35 on EC proliferation and migration. Conclusion Our study revealed a novel mechanism through which IFI35 affects the proliferation and migration of ECs as well as neointima formation, specifically through inhibition of the NF‐κB/p65 pathway. Thus, IFI35 is a promising target for the prevention and treatment of post‐injury vascular intimal hyperplasia.