期刊
WOUND REPAIR AND REGENERATION
卷 15, 期 5, 页码 636-645出版社
BLACKWELL PUBLISHING
DOI: 10.1111/j.1524-475X.2007.00278.x
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资金
- NCI NIH HHS [CA85249] Funding Source: Medline
- NIDDK NIH HHS [F32DK71406] Funding Source: Medline
- NIGMS NIH HHS [R01GM068778] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA085249] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [F32DK071406] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM068778] Funding Source: NIH RePORTER
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.
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