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Downregulation of hypoxia-inducible factor-1α by RNA interference alleviates the development of collagen-induced arthritis in rats

Hu, Yiping, Zhang, Tiantian, Chen, Jingqin, Cheng, WenXiang, Chen, Jianhai, Zheng, Zhengtan, Lin, Jietao, Zhu, Guoyuan, Zhang, Yong, Bai, Xueling, Wang, Yan, Song, Bing, Wang, Qingwen, Qin, Ling and Zhang, Peng 2020. Downregulation of hypoxia-inducible factor-1α by RNA interference alleviates the development of collagen-induced arthritis in rats. Molecular Therapy - Nucleic Acids 19 , pp. 1330-1342. 10.1016/j.omtn.2020.01.014

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Abstract

Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. Hypoxia-inducible factor-1α (HIF-1α) as a transcription factor in response to hypoxia suggests that it could be a potential therapeutic target for the treatment of RA. In this study, we assessed whether the HIF pathway blockade attenuates the manifestations of RA in the collagen-induced arthritis (CIA) rat model. We constructed a short hairpin RNA (shRNA) lentiviral expression vector targeting HIF-1α (pLVX-shRNA-HIF-1α) and to achieve HIF-1α RNA interference. Quantitative RT-PCR, immunofluorescence staining, and western blot were used to detect the expressions of HIF-1α, vascular endothelial growth factor (VEGF), phsopho (p)-p65, and p-IКBɑ mRNA and protein, respectively. Micro-computed tomography was used to investigate joint morphology at different time points after CIA induction. Moreover, enzyme-linked immunosorbent assay (ELISA) was used to monitor the expression of inflammatory cytokines. In vitro analyses revealed that pLVX-shRNA-HIF-1α effectively inhibited the expression of HIF-1α and VEGF and led to the activation of p-65 and p-IКBɑ, as well as decreased proinflammatory cytokine expression in cell culture. Inhibition of HIF-1α in rats decreased signs of a systemic inflammatory condition, together with decreased pathological changes of RA. Moreover, downregulation of HIF-1α expression markedly reduced the synovitis and angiogenesis. In conclusion, we have shown that pharmacological inhibition of HIF-1 may improve the clinical manifestations of RA.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Publisher: Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group
ISSN: 2162-2531
Date of First Compliant Deposit: 2 March 2020
Date of Acceptance: 10 January 2020
Last Modified: 02 Mar 2020 12:15
URI: http://orca.cf.ac.uk/id/eprint/130073

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