The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues.
Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1alpha functional activity was specifically caused by impaired HIF-1alpha binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1alpha/p300 interaction and transactivation by HIF-1alpha. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention.
Thangarajah
Hariharan
H
Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, GK-201, Stanford, CA 94305, USA.
Yao
Dachun
D
Chang
Edward I
EI
Shi
Yubin
Y
Jazayeri
Leila
L
Vial
Ivan N
IN
Galiano
Robert D
RD
Du
Xue-Liang
XL
Grogan
Raymon
R
Galvez
Michael G
MG
Januszyk
Michael
M
Brownlee
Michael
M
Gurtner
Geoffrey C
GC
D000818:Animals; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology*; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000150:complications / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011765:Pyruvaldehyde / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D011765:Pyruvaldehyde; D050880:p300-CBP Transcription Factors; D005947:Glucose; D003676:Deferoxamine