title: Hyperbaric oxygen therapy activates hypoxia-inducible factor 1 (HIF-1), which contributes to improved wound healing in diabetic mice.
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, SKRC7 cells, and HIF-1α knock-out and wild-type mouse embryonic fibroblasts using appropriate techniques (Western 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.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
authors.forename: Vivekananda Gupta
authors.initials: VG
authors.lastname: Sunkari
authors.forename: Folke
authors.initials: F
authors.lastname: Lind
authors.forename: Ileana Ruxandra
authors.initials: IR
authors.lastname: Botusan
authors.forename: Abad
authors.initials: A
authors.lastname: Kashif
authors.forename: Zhao-Jun
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.forename: Omaida
authors.initials: O
authors.lastname: Velazquez
authors.forename: Sergiu-Bogdan
authors.initials: SB
authors.lastname: Catrina
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D017719:Diabetic Foot / Q000378:metabolism / Q000473:pathology*; D006931:Hyperbaric Oxygenation; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D014945:Wound Healing
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit