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Sustained expression ofHif-1αin the diabetic environment promotes angiogenesis and cutaneous wound repair
- Source :
- Wound Repair and Regeneration. 15:636-645
- Publication Year :
- 2007
- Publisher :
- Wiley, 2007.
-
Abstract
- 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.
- Subjects :
- Vascular Endothelial Growth Factor A
medicine.medical_specialty
Transcription, Genetic
Angiogenesis
Neovascularization, Physiologic
Nitric Oxide Synthase Type II
Mice, Inbred Strains
Dermatology
Neovascularization
Mice
chemistry.chemical_compound
Internal medicine
Diabetes Mellitus
medicine
Animals
Transcription factor
Cell Proliferation
Wound Healing
Leptin Deficiency
biology
Reverse Transcriptase Polymerase Chain Reaction
Leptin
Membrane Proteins
Fibroblasts
Hypoxia-Inducible Factor 1, alpha Subunit
Nitric oxide synthase
Vascular endothelial growth factor
Disease Models, Animal
Endocrinology
chemistry
Immunology
biology.protein
Receptors, Leptin
Surgery
medicine.symptom
Wound healing
Heme Oxygenase-1
Subjects
Details
- ISSN :
- 1524475X and 10671927
- Volume :
- 15
- Database :
- OpenAIRE
- Journal :
- Wound Repair and Regeneration
- Accession number :
- edsair.doi.dedup.....2ed694f39828faf507bfe462cb7725e0