Downregulation of Hypoxia-Inducible Factor-1α by RNA Interference Alleviates the Development of Collagen-Induced Arthritis in Rats

Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) 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-1 alpha (pLVX-shRNA-HIF-1 alpha) and to achieve HIF-1 alpha RNA interference. Quantitative RT-PCR, immunofluorescence staining, and western blot were used to detect the expressions of HIF-1 alpha, vascular endothelial growth factor (VEGF), phsopho (p)-p65, and p-IKB alpha 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-1 alpha effectively inhibited the expression of HIF-1 alpha and VEGF and led to the activation of p-65 and p-IKB alpha, as well as decreased proinflammatory cytokine expression in cell culture. Inhibition of HIF-1 alpha in rats decreased signs of a systemic inflammatory condition, together with decreased pathological changes of RA. Moreover, downregulation of HIF-1 alpha 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.