title: Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia.
abstract: 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.
authors.affiliation: Diabetes and Metabolism Division, Baker Epigenetics in Human Health and Disease, Baker IDI Heart and Diabetes Institute, Alfred Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia. assam.el-osta@bakeridi.edu.au
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Daniella
authors.initials: D
authors.lastname: Brasacchio
authors.forename: Dachun
authors.initials: D
authors.lastname: Yao
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
authors.forename: Peter L
authors.initials: PL
authors.lastname: Jones
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000235:genetics / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011496:Protein Methyltransferases; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018932:Chemokine CCL2; D005947:Glucose; D006442:Glycated Hemoglobin; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D007473:Ion Channels; D024101:Mitochondrial Proteins; D011496:Protein Methyltransferases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D051996:Transcription Factor RelA; D000071256:Uncoupling Protein 1; D019010:Vascular Cell Adhesion Molecule-1; C111835:CCL2 protein, human; C517652:hemoglobin A1c protein, human