Mechanisms and meaning of activation of Hypoxia-Inducible-Factor-1 (HIF-1) in muscle after mechanical trauma

在机械性肌肉损伤过程中，由于血管破裂或水肿压迫而形成缺氧区。缺氧组织区域的基因表达是通过激活缺氧诱导因子1 （HIF-1）来协调的。特别是从血管外渗到缺氧组织的白细胞依赖于HIF-1激活的基因表达来发挥其正常功能。在髓细胞或肌肉细胞中靶向缺失HIF-1α （HIF-1的氧调节亚基）的小鼠被用于闭合性肌肉损伤模型。髓细胞中HIF-1α的敲除揭示了白细胞外渗和再生开始的主要延迟。没有HIF-1α的肌肉细胞往往损伤更快，但也更早开始再生。HIF-1α及其同源物HIF-2α的免疫组织化学显示，HIF-2α阳性细胞在创伤后7天内明显增加。我们现在将研究HIF-2α的骨髓特异性敲除。此外，缺乏负责HIF-α降解的髓系von-Hippel-Lindau蛋白的小鼠将被测试在肌肉创伤中白细胞中高HIF-1/2α水平的影响。由于增加HIF-1/2α的药物已经进入临床试验阶段，我们的研究可能为机械肌肉损伤的此类治疗提供依据。

During the course of mechanical muscle trauma hypoxic regions develop due to the rupture of blood vessels or their compression by oedema. Gene expression in hypoxic tissue areas is coordinated through activation of hypoxia-inducible factor 1 (HIF-1). In particular leukocytes that extravasate from the vessels into the hypoxic tissue depend on HIF-1 activated gene expression for their proper function. Mice with targeted deletion of HIF-1α, the oxygen regulated subunit of HIF-1, either in myeloid or muscle cells were used in a model of closed muscle trauma. Knockout of HIF-1α in myeloid cells revealed a major delay in the extravasation of leukocytes and the onset of regeneration. Muscle cells without HIF-1α tended to be damaged more rapidly but to also started regeneration earlier. Immuno-histochemistry for HIF-1α and its homolog HIF-2α revealed a pronounce increase in HIF-2α positive cells up to 7 days after a trauma. We will now study a myeloid specific knockout of HIF-2α. In addition, mice that lack myeloid von-Hippel-Lindau protein that is responsible for HIF-α degradation will be tested for the effect of high HIF-1/2α levels in leukocytes in muscle trauma. Since drugs that increase HIF-1/2α are already in clinical testing, our studies may provide the basis for such kind of treatment in mechanical muscle trauma.