The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues

被引:369
作者
Thangarajah, Hariharan [1 ]
Yao, Dachun [2 ]
Chang, Edward I. [1 ]
Shi, Yubin [1 ]
Jazayeri, Leila [1 ]
Vial, Ivan N. [1 ]
Galiano, Robert D. [1 ]
Du, Xue-Liang [2 ]
Grogan, Raymon [1 ]
Galvez, Michael G. [1 ]
Januszyk, Michael [1 ]
Brownlee, Michael [2 ]
Gurtner, Geoffrey C. [1 ]
机构
[1] Stanford Univ, Sch Med, Dept Surg, Stanford, CA 94305 USA
[2] Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA
关键词
deferoxamine; HIF-1; hyperglycemia; ischemia; ENDOTHELIAL GROWTH-FACTOR; INDUCIBLE FACTOR-1; VESSEL FORMATION; MELLITUS; COMPLICATIONS; TRANSCRIPTION; HYDROXYLASES; STABILIZATION; MOBILIZATION; METABOLISM;
D O I
10.1073/pnas.0906670106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-1 alpha (HIF-1 alpha), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1 alpha functional activity was specifically caused by impaired HIF-1 alpha 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-1 alpha/p300 interaction and transactivation by HIF-1 alpha. 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.
引用
收藏
页码:13505 / 13510
页数:6
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