Effects of decreased insulin-like growth factor-1 stimulation on hypoxia inducible factor 1-alpha protein synthesis and function during cutaneous repair in diabetic mice.
Insulin-like growth factor-1 (Igf-1), a critical mediator of tissue repair, is significantly decreased in diabetic wounds. Furthermore, decreased levels of hypoxia-inducible factor 1-alpha (Hif-1alpha) and its target genes are also associated with impaired wound healing in diabetic mice. The aim of our study was to examine whether the reduced levels of Igf-1 are responsible for the reduction in Hif-1alpha protein synthesis and activity in diabetic wounds. We provide evidence that Igf-1 regulates Hif-1alpha protein synthesis and activity during wound repair. In addition, Igf-1 stimulated phosphytidylinositol 3-kinase activity in diabetic fibroblasts, which, in turn, increased activation of the translational regulatory protein, p70 S6 kinase. Moreover, improved healing of diabetic wounds by addition of recombinant IGF-1 protein was associated with an increase in Hif-1alpha protein synthesis and function in vivo.
Yu
Diana H
DH
Surgical Research Laboratory at San Francisco General Hospital, Department of Surgery, University of California-San Francisco, San Francisco, California 94143-1302, USA.
Mace
Kimberly A
KA
Hansen
Scott L
SL
Boudreau
Nancy
N
Young
David M
DM
D000818:Animals; D015153:Blotting, Western; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D054411:Receptors, Leptin / Q000172:deficiency; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D012867:Skin / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D014945:Wound Healing / Q000502:physiology*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D054411:Receptors, Leptin; D042461:Vascular Endothelial Growth Factor A; C515447:leptin receptor, mouse; C467480:vascular endothelial growth factor A, mouse; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa