The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues
The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues
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DOI：
10.1073/pnas.0906670106
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发表时间：
2009-08-11
影响因子：
11.1
通讯作者：
Gurtner, Geoffrey C.
中科院分区：
文献类型：
--
作者：
Thangarajah, Hariharan;Yao, Dachun;Gurtner, Geoffrey C.
糖尿病与急性血管闭塞事件后的不良结局相关。这部分是由于未能形成足够的代偿性微脉管系统来应对缺血。由于血管内皮生长因子（VEGF）是新血管形成的重要介质，我们检查了糖尿病中 VEGF 的缺氧上调是否受损。从 2 型糖尿病患者中分离出的成纤维细胞和长期暴露于高葡萄糖的正常成纤维细胞在缺氧时上调 VEGF 的能力均存在缺陷。在体内，糖尿病动物表现出响应软组织缺血而增加 VEGF 产生的能力受损。这是由于高葡萄糖诱导转录因子缺氧诱导因子 1 α (HIF-1 α) 的反式激活减少所致，该转录因子介导缺氧刺激的 VEGF 表达。 HIF-1 α 功能活性降低具体是由于 HIF-1 α 与共激活因子 p300 的结合受损所致。我们确定二羰基代谢物甲基乙二醛对 p300 的共价修饰是导致这种关联减少的原因。施用去铁胺可消除甲基乙二醛缀合，使 HIF-1 α/p300 相互作用和 HIF-1 α 反式激活正常化。在糖尿病小鼠中，去铁胺促进新血管形成并增强伤口愈合。这些发现明确了糖尿病组织中 VEGF 生成受损的分子缺陷，并为治疗干预提供了有希望的方向。
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.