Aldose Reductase Drives Hyperacetylation of Egr-1 in Hyperglycemia and Consequent Upregulation of Proinflammatory and Prothrombotic Signals
- Srinivasan Vedantham1,
- Devi Thiagarajan1,
- Radha Ananthakrishnan1,
- Lingjie Wang1,
- Rosa Rosario1,
- Yu Shan Zou1,
- Ira Goldberg2,
- Shi Fang Yan1,
- Ann Marie Schmidt1 and
- Ravichandran Ramasamy1⇑
- 1Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY
- 2Division of Preventive Medicine and Nutrition, Columbia University Medical Center, New York, NY
- Corresponding author: Ravichandran Ramasamy, .
S.V., D.T., and R.A. contributed equally to this work.
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.
See accompanying commentary, p. 402.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0032/-/DC1.
- Received January 11, 2013.
- Accepted October 3, 2013.
- © 2014 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.