High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A

Dachun Yao, Tetsuya Taguchi, Takeshi Matsumura, Richard Pestell, Diane Edelstein, Ida Giardino, Guntram Suske, Naila Rabbani, Paul J. Thornalley, Vijay P. Sarthy, Hans Peter Hammes, Michael Brownlee

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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 byO-linkedN-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 α. This novel mechanism for regulating gene expression may play a role in the pathobiology of diabetic vascular disease.

Original languageEnglish (US)
Pages (from-to)31038-31045
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number42
DOIs
StatePublished - Oct 19 2007

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Angiopoietin-2
Pyruvaldehyde
Endothelial cells
Transcription
Endothelial Cells
Glucose
Trioses
Kidney
Diabetic Angiopathies
Co-Repressor Proteins
Acetylglucosamine
Vascular Cell Adhesion Molecule-1
Glycolysis
Gene expression
Arginine
Adhesion
Tumor Necrosis Factor-alpha
Phosphates
Gene Expression
Degradation

ASJC Scopus subject areas

  • Biochemistry

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High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. / 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; Brownlee, Michael.

In: Journal of Biological Chemistry, Vol. 282, No. 42, 19.10.2007, p. 31038-31045.

Research output: Contribution to journalArticle

Yao, D, Taguchi, T, Matsumura, T, Pestell, R, Edelstein, D, Giardino, I, Suske, G, Rabbani, N, Thornalley, PJ, Sarthy, VP, Hammes, HP & Brownlee, M 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. https://doi.org/10.1074/jbc.M704703200
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 ; Brownlee, Michael. / High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 42. pp. 31038-31045.
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