Hyperglycemia induces p65 in endothelium
Kofi
J Exp Med. 2008 Sep 29;205(10):2409-17. Epub 2008 Sep 22
Erratum in:
* J Exp Med. 2008 Oct 27;205(11):2683.
Transient high glucose causes persistent epigenetic changes and altered
gene expression during subsequent normoglycemia.
El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, Cooper ME,
Brownlee M.
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.
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.
Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
PMID: 18809715