Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and
consequent upregulation of proinflammatory and prothrombotic signals.
Authors Vedantham S, Thiagarajan D, Ananthakrishnan R, Wang L, Rosario R, Zou YS,
Goldberg I, Yan SF, Schmidt AM, Ramasamy R
Submitted By Submitted Externally on 4/15/2014
Status Published
Journal Diabetes
Year 2014
Date Published 2/1/2014
Volume : Pages 63 : 761 - 774
PubMed Reference 24186862
Abstract Sustained increases in glucose flux via the aldose reductase (AR) pathway have
been linked to diabetic vascular complications. Previous studies revealed that
glucose flux via AR mediates endothelial dysfunction and leads to lesional
hemorrhage in diabetic human AR (hAR) expressing mice in an apoE(-/-)
background. Our studies revealed sustained activation of Egr-1 with subsequent
induction of its downstream target genes tissue factor (TF) and vascular cell
adhesion molecule-1 (VCAM-1) in diabetic apoE(-/-)hAR mice aortas and in high
glucose-treated primary murine aortic endothelial cells expressing hAR.
Furthermore, we observed that flux via AR impaired NAD(+) homeostasis and
reduced activity of NAD(+)-dependent deacetylase Sirt-1 leading to acetylation
and prolonged expression of Egr-1 in hyperglycemic conditions. In conclusion,
our data demonstrate a novel mechanism by which glucose flux via AR triggers
activation, acetylation, and prolonged expression of Egr-1 leading to
proinflammatory and prothrombotic responses in diabetic atherosclerosis.

Investigators with authorship
Ira GoldbergNew York University School of Medicine

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