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 ORCID: https://orcid.org/0000-0001-9356-2333, 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:	11 Oct 2023 19:41
URI:	https://orca.cardiff.ac.uk/id/eprint/130073

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