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Department of Cell and Developmental Biology

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Animals; Blood Glucose; Cattle; Cells, Cultured; Chemokine CCL2; Diabetes Complications; Diabetes Mellitus; Endothelial Cells; *Epigenesis, Genetic; *Gene Expression Regulation; Glucose; Hemoglobin A, Glycosylated; Histone-Lysine N-Methyltransferase; Humans; Hyperglycemia; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Proteins; Promoter Regions, Genetic; Protein Methyltransferases; Reactive Oxygen Species; Risk Factors; Superoxide Dismutase; Transcription Factor RelA; Vascular Cell Adhesion Molecule-1


Cell Biology | Developmental Biology | Endocrine System Diseases | Molecular Biology | Molecular Genetics


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 kappaB (NF-kappaB) 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-kappaB-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 alpha-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.

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DOI of Published Version



J Exp Med. Sep 29, 2008; 205(10): 2409–2417. doi: 10.1084/jem.20081188Link to article on publisher's site

Journal/Book/Conference Title

The Journal of experimental medicine


At the time of publication, Peter Jones was not yet affiliated with the University of Massachusetts Medical School.

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Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.