Transient high glucose causes persistent vascular dysfunction and delayed wound healing by the DNMT1-mediated Ang-1/NF-κB pathway
Transient high glucose causes persistent vascular dysfunction and delayed wound healing by the DNMT1-mediated Ang-1/NF-κB pathway
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短暂的高血糖通过 DNMT1 介导的 Ang-1/NF-κB 通路导致持续的血管功能障碍和伤口愈合延迟
DOI：
10.1016/j.jid.2020.10.023
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发表时间：
2020
影响因子：
6.5
通讯作者：
Qi Shaohai
中科院分区：
文献类型：
--
作者：
Zhao Jingling;Yang Shuai;Shu Bin;Chen Lei;Yang Ronghua;Xu Yingbin;Xie Julin;Liu Xusheng;Qi Shaohai
尽管高血糖终止，但糖尿病并发症的进展并未停止，提示代谢记忆现象。然而，代谢记忆是否存在并影响糖尿病伤口的愈合，以及其潜在的分子机制尚不清楚。在这项研究中，我们发现，尽管血糖控制正常化，但糖尿病小鼠的伤口愈合延迟，血管生成减少。因此，我们假设短暂的高血糖峰值可能是糖尿病伤口愈合的一个危险因素。我们发现短暂性高血糖会对血管内皮造成持续性损伤。短暂性高血糖直接上调DNMT1的表达，导致Ang-1的高甲基化和Ang-1表达的降低，进而诱导NF-κB的长期激活和随后的内皮功能障碍。体内研究进一步表明，抑制DNMT1可通过调节Ang-1/NF-κB信号通路促进血管生成，加速糖尿病创面愈合。这些结果强调了短暂性高血糖峰值对伤口愈合的显著而持久的影响，并表明DNMT1是糖尿病血管并发症的靶点。
The progression of diabetic complications does not halt despite the termination of hyperglycemia, suggesting a metabolic memory phenomenon. However, whether metabolic memory exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that wound healing was delayed, and angiogenesis was decreased in mice with diabetes despite the normalization of glycemic control. Thus, we hypothesized that transient hyperglycemic spikes may be a risk factor for diabetic wound healing. We showed that transient hyperglycemia caused persistent damage to the vascular endothelium. Transient hyperglycemia directly upregulated DNMT1 expression, leading to the hypermethylation of Ang-1 and reduced Ang-1 expression, which in turn induced long-lasting activation of NF-κB and subsequent endothelial dysfunction. An in vivo study further showed that inhibition of DNMT1 promoted angiogenesis and accelerated diabetic wound healing by regulating the Ang-1/NF-κB signaling pathway. These results highlight the dramatic and long-lasting effects of transient hyperglycemic spikes on wound healing and suggest that DNMT1 is a target for diabetic vascular complications.