Department of Rheumatology and Clinical Immunology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Curr Med Chem. 2010;17(3):254-63. doi: 10.2174/092986710790149783.
Angiogenesis plays an important role in the pathogenesis of inflammatory diseases, including rheumatoid arthritis (RA). The site and extent of inflammation and subsequent joint destruction in the rheumatoid synovium is dependent on the development of new vasculature. Inhibition of angiogenesis, extensively studied in cancer, might therefore be of interest as treatment option for RA. Hypoxia-inducible factor-1 (HIF-1) has been reported to play a critical role in the regulation of hypoxia driven angiogenesis. HIF-1 is a transcription factor that is constitutively expressed in many cells. It gains transcriptional activity in hypoxic cells leading to the expression of genes involved in angiogenesis. The synovium is hypoxic, but also in an inflammatory environment such as seen in RA, inflammatory cytokines may be important inducers of HIF-1 expression and/or activation. Many drugs currently used in the treatment of RA have anti-angiogenic effects, which are exerted at different levels. Blocking of TNF-alpha, for instance, reduces TNF-alpha induced VEGF production. Studies aiming at direct inhibition of pro-angiogenic factors, such as inhibiting VEGF- or FGF-receptor signalling or blocking VEGF by monoclonal anti-VEGF antibody therapeutics, are in progress. Inhibition of HIF-1 expression or activation, either by blocking signal transduction pathways leading to HIF-1 induction or by inhibiting accumulation of HIF -1 protein, represents a new strategy, which is of interest for the treatment of RA. This review will concisely summarize the general knowledge on the molecular control of gene expression by HIF-1, its involvement in RA, and potential for therapeutic intervention at the level of HIF-1 activity.
血管生成在炎症性疾病的发病机制中起着重要作用，包括类风湿关节炎（RA）。类风湿滑膜中炎症的部位和程度以及随后的关节破坏取决于新血管的发育。因此，广泛研究用于癌症的血管生成抑制可能是 RA 的一种治疗选择。缺氧诱导因子-1（HIF-1）已被报道在调节缺氧驱动的血管生成中起关键作用。HIF-1 是一种在许多细胞中持续表达的转录因子。它在缺氧细胞中获得转录活性，导致参与血管生成的基因表达。滑膜缺氧，但在 RA 等炎症环境中，炎症细胞因子可能是 HIF-1 表达和/或激活的重要诱导剂。目前用于治疗 RA 的许多药物具有抗血管生成作用，这些作用在不同水平上发挥。例如，阻断 TNF-α可减少 TNF-α诱导的 VEGF 产生。旨在直接抑制促血管生成因子的研究，如抑制 VEGF 或 FGF 受体信号传导或通过单克隆抗 VEGF 抗体治疗剂阻断 VEGF，正在进行中。抑制 HIF-1 的表达或激活，无论是通过阻断导致 HIF-1 诱导的信号转导途径还是通过抑制 HIF-1 蛋白的积累，都代表了一种新的策略，这对于治疗 RA 具有重要意义。本文将简要总结 HIF-1 对基因表达的分子控制、其在 RA 中的作用以及在 HIF-1 活性水平进行治疗干预的潜力的一般知识。
