Sustained expression of Hif-1α in the diabetic environment promotes angiogenesis and cutaneous wound repair
Sustained expression of Hif-1α in the diabetic environment promotes angiogenesis and cutaneous wound repair
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DOI：
10.1111/j.1524-475x.2007.00278.x
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发表时间：
2007-09-01
影响因子：
2.9
通讯作者：
Young, David M.
中科院分区：
文献类型：
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作者：
Mace, Kimberly A.;Yu, Diana H.;Young, David M.
糖尿病患者创面愈合受损与缺乏参与细胞增殖和迁移的因子有关，如血管内皮生长因子。然而，目前尚不清楚编码这些因子的基因的转录调控如何受到糖尿病环境的影响。低氧诱导因子-1α(Hif-1α)是Hif-1转录因子的调节亚单位，在这些基因的激活过程中起着重要作用。因此，我们测试了Hif-1α功能在糖尿病创面环境中是否受损，以及恢复Hif-1功能是否促进了创面愈合。在这里，我们表明，与非糖尿病小鼠相比，瘦素受体缺陷糖尿病小鼠伤口中Hif-1α蛋白水平显著降低。Hif-1α水平的降低会导致DNA结合活性的降低，并导致几个Hif-1靶基因的表达减少，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。此外，我们证明，在瘦素受体缺陷的糖尿病创面持续表达Hif-1α可以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着重要作用，Hif-1α水平降低可能有助于创面愈合受损。
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-1 alpha (Hif-1 alpha), the regulatory subunit of the Hif-1 transcription factor, plays an important role in activating many of these genes. Therefore, we tested whether Hif-1 alpha function is impaired in the diabetic wound environment and whether restoring Hif-1 function improves wound healing. Here, we show that Hif-1 alpha protein levels are dramatically reduced in wounds of leptin receptor-deficient diabetic mice compared with nondiabetic littermates. Reduction in Hif-1 alpha 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-1 alpha 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-1 alpha function plays a significant role in wound healing and reduced levels of Hif-1 alpha may contribute to impaired healing.