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. 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.

中文翻译：

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RNA 干扰下调缺氧诱导因子 1α 可减轻大鼠胶原诱导关节炎的发展


类风湿性关节炎（RA）是最常见的自身免疫性关节炎类型。缺氧诱导因子-1α（HIF-1α）作为缺氧反应的转录因子表明它可能是治疗 RA 的潜在治疗靶点。在这项研究中，我们评估了 HIF 通路阻断是否会减轻胶原诱导关节炎 (CIA) 大鼠模型中 RA 的表现。我们构建了靶向HIF-1α的短发夹RNA（shRNA）慢病毒表达载体（pLVX-shRNA-HIF-1α）并实现HIF-1α的RNA干扰。定量RT-PCR、免疫荧光染色和Western blot分别检测HIF-1α、血管内皮生长因子（VEGF）、phsopho（p）-p65和p-IКBɑ mRNA和蛋白的表达。使用微型计算机断层扫描来研究 CIA 诱导后不同时间点的关节形态。此外，酶联免疫吸附测定（ELISA）用于监测炎症细胞因子的表达。分析表明，pLVX-shRNA-HIF-1α 有效抑制 HIF-1α 和 VEGF 的表达，导致 p-65 和 p-IКBɑ 激活，并降低细胞培养物中促炎细胞因子的表达。抑制大鼠体内的 HIF-1α 可减少全身炎症症状，同时减少 RA 的病理变化。此外，HIF-1α表达的下调显着减少了滑膜炎和血管生成。总之，我们已经证明 HIF-1 的药理学抑制可以改善 RA 的临床表现。