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High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A
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Yao, Dachun, Taguchi, Tetsuya, Matsumura, Takeshi, Pestell, Richard, Edelstein, Diane, Giardino, Ida, Suske, Guntram, Rabbani, Naila, Thornalley, Paul J., Sarthy, Vijay P., Hammes, Hans-Peter and Brownlee, Michael (2007) High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. Journal of Biological Chemistry, Vol.282 (No.42). pp. 31038-31045. doi:10.1074/jbc.M704703200
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Official URL: http://dx.doi.org/10.1074/jbc.M704703200
Abstract
Methylglyoxal is a highly reactive dicarbonyl degradation product formed from triose phosphates during glycolysis. Methylglyoxal forms stable adducts primarily with arginine residues of intracellular proteins. The biologic role of this covalent modification in regulating cell function is not known. Here we report that in mouse kidney endothelial cells, high glucose causes increased methylglyoxal modification of the corepressor mSin3A. Methylglyoxal modification of mSin3A results in increased recruitment of O-GlcNAc-transferase, with consequent increased modification of Sp3 by O-linked N-acetylglucosamine. This modification of Sp3 causes decreased binding to a glucose-responsive GC-box in the angiopoietin-2 (Ang-2) promoter, resulting in increased Ang-2 expression. Increased Ang-2 expression induced by high glucose increased expression of intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 in cells and in kidneys from diabetic mice and sensitized microvascular endothelial cells to the proinflammatory effects of tumor necrosis factor alpha. This novel mechanism for regulating gene expression may play a role in the pathobiology of diabetic vascular disease.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QD Chemistry | ||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Journal of Biological Chemistry | ||||
| Publisher: | American Society for Biochemistry and Molecular Biology | ||||
| ISSN: | 0021-9258 | ||||
| Official Date: | 19 October 2007 | ||||
| Dates: |
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| Volume: | Vol.282 | ||||
| Number: | No.42 | ||||
| Number of Pages: | 8 | ||||
| Page Range: | pp. 31038-31045 | ||||
| DOI: | 10.1074/jbc.M704703200 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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