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Hyperbaric oxygen therapy activates hypoxia‐inducible factor 1 ( HIF ‐1), which contributes to improved wound healing in diabetic mice
Author(s) -
Sunkari Vivekananda Gupta,
Lind Folke,
Botusan Ileana Ruxandra,
Kashif Abad,
Liu ZhaoJun,
YläHerttuala Seppo,
Brismar Kerstin,
Velazquez Omaida,
Catrina SergiuBogdan
Publication year - 2015
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/wrr.12253
Subject(s) - wound healing , hypoxia inducible factors , progenitor cell , angiogenesis , western blot , bone marrow , stromal cell , basic fibroblast growth factor , in vivo , growth factor , cancer research , chemistry , pharmacology , immunology , medicine , microbiology and biotechnology , biology , stem cell , receptor , biochemistry , gene
Abstract Hyperbaric oxygen ( HBO ) therapy has been used as an adjunctive therapy for diabetic foot ulcers, although its mechanism of action is not completely understood. Recently, it has been shown that HBO mobilizes the endothelial progenitor cells ( EPCs ) from bone marrow that eventually will aggregate in the wound. However, the gathering of the EPCs in diabetic wounds is impaired because of the decreased levels of local stromal‐derived factor‐1α ( SDF ‐1α). Therefore, we investigated the influence of HBO on hypoxia‐inducible factor 1 ( HIF ‐1), which is a central regulator of SDF ‐1α and is down‐regulated in diabetic wounds. The effects of HBO on HIF ‐1α function were studied in human dermal fibroblasts, SKRC 7 cells, and HIF ‐1α knock‐out and wild‐type mouse embryonic fibroblasts using appropriate techniques ( W estern blot, quantitative polymerase chain reaction, and luciferase hypoxia‐responsive element reporter assay). Cellular proliferation was assessed using H 3 ‐thymidine incorporation assay. The effect of HIF in combination with HBOT was tested by inoculating stable HIF ‐1α‐expressing adenovirus (Adv‐ HIF ) into experimental wounds in db/db mice exposed to HBO . HBO activates HIF ‐1α at several levels by increasing both HIF ‐1α stability (by a non‐canonical mechanism) and activity (as shown both by induction of relevant target genes and by a specific reporter assay). HIF ‐1α induction has important biological relevance because the induction of fibroblast proliferation in HBO disappears when HIF ‐1α is knocked down. Moreover, the local transfer of stable HIF ‐1α‐expressing adenovirus (Adv‐ HIF ) into experimental wounds in diabetic (db/db mice) animals has an additive effect on HBO ‐mediated improvements in wound healing. In conclusion, HBO stabilizes and activates HIF ‐1, which contributes to increased cellular proliferation. In diabetic animals, the local transfer of active HIF further improves the effects of HBO on wound healing.