Aldose Reductase Drives Hyperacetylation of Egr-1 in Hyperglycemia and Consequent Upregulation of Proinflammatory and Prothrombotic Signals

  1. Ravichandran Ramasamy1
  1. 1Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY
  2. 2Division of Preventive Medicine and Nutrition, Columbia University Medical Center, New York, NY
  1. Corresponding author: Ravichandran Ramasamy, ramasr02{at}nyumc.org.
  1. S.V., D.T., and R.A. contributed equally to this work.

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.

Footnotes

  • Received January 11, 2013.
  • Accepted October 3, 2013.

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  1. Diabetes vol. 63 no. 2 761-774
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