Mace Kimberly A, Yu Diana H, Paydar Keyianoosh Z, Boudreau Nancy, Young David M
Department of Surgery, University of California San Francisco, San Francisco, California 94143-0932, USA.
Wound Repair Regen. 2007 Sep-Oct;15(5):636-45. doi: 10.1111/j.1524-475X.2007.00278.x.
Impaired wound healing in diabetic patients is associated with deficiencies in the production of factors involved in cell proliferation and migration, such as vascular endothelial growth factor. However, it remains unclear how the transcriptional regulation of the genes encoding these factors is affected by the diabetic environment. Hypoxia-inducible factor-1alpha (Hif-1alpha), the regulatory subunit of the Hif-1 transcription factor, plays an important role in activating many of these genes. Therefore, we tested whether Hif-1alpha function is impaired in the diabetic wound environment and whether restoring Hif-1 function improves wound healing. Here, we show that Hif-1alpha protein levels are dramatically reduced in wounds of leptin receptor-deficient diabetic mice compared with nondiabetic littermates. Reduction in Hif-1alpha levels results in decreased DNA-binding activity and in decreased expression of several Hif-1 target genes, including vascular endothelial growth factor, heme oxygenase-1, and inducible nitric oxide synthase. Furthermore, we demonstrate that sustained expression of Hif-1alpha in leptin receptor-deficient diabetic wounds restores expression of these factors, enhances angiogenesis, and significantly accelerates wound healing. Taken together, these results suggest that Hif-1alpha function plays a significant role in wound healing and reduced levels of Hif-1alpha may contribute to impaired healing.
糖尿病患者伤口愈合受损与细胞增殖和迁移相关因子（如血管内皮生长因子）生成不足有关。然而，编码这些因子的基因的转录调控如何受糖尿病环境影响仍不清楚。缺氧诱导因子-1α（Hif-1α）是Hif-1转录因子的调节亚基，在激活许多此类基因中起重要作用。因此，我们测试了Hif-1α功能在糖尿病伤口环境中是否受损，以及恢复Hif-1功能是否能改善伤口愈合。在此，我们表明，与非糖尿病同窝小鼠相比，瘦素受体缺陷型糖尿病小鼠伤口中的Hif-1α蛋白水平显著降低。Hif-1α水平降低导致DNA结合活性降低以及包括血管内皮生长因子、血红素加氧酶-1和诱导型一氧化氮合酶在内的几种Hif-1靶基因的表达降低。此外，我们证明在瘦素受体缺陷型糖尿病伤口中持续表达Hif-1α可恢复这些因子的表达，增强血管生成，并显著加速伤口愈合。综上所述，这些结果表明Hif-1α功能在伤口愈合中起重要作用，Hif-1α水平降低可能导致愈合受损。
