Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia.
Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia.
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DOI：
10.1084/jem.20081188
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发表时间：
2008-09-29
期刊：
影响因子：
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通讯作者：
Brownlee M
中科院分区：
文献类型：
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作者：
El-Osta A;Brasacchio D;Yao D;Pocai A;Jones PL;Roeder RG;Cooper ME;Brownlee M
目前糖尿病治疗的目标是降低HbA 1c的时间平均水平，以预防糖尿病并发症。然而，HbA 1c仅解释了并发症风险变化的<25%。由于调整平均血糖后HbA 1c与血糖变异性不相关，我们假设一过性高血糖峰值可能是糖尿病并发症的HbA 1c独立风险因素。我们发现，短暂的高血糖诱导核因子κB（NF-κB）亚基p65启动子的长期激活表观遗传学变化在体外和非糖尿病小鼠的主动脉内皮细胞，这导致p65基因表达增加。表观遗传学变化和基因表达变化持续至少6天的后续正常妊娠，如NF-κ B诱导的单核细胞趋化蛋白1和血管细胞粘附分子1表达的增加。通过减少线粒体超氧化物产生或超氧化物诱导的α-氧代醛来预防高血糖诱导的表观遗传变化和p65表达增加。这些结果突出了短期高血糖峰值对血管细胞的显著和持久影响，并表明短暂的高血糖峰值可能是糖尿病并发症的HbA 1c独立风险因素。
The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor κB (NF-κB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-κB–induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced α-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications.