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J. Biol. Chem., Vol. 282, Issue 42, 31038-31045, October 19, 2007

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High Glucose Increases Angiopoietin-2 Transcription in Microvascular Endothelial Cells through Methylglyoxal Modification of mSin3A^*

Dachun Yao¹, Tetsuya Taguchi¹, Takeshi Matsumura, Richard Pestell, Diane Edelstein, Ida Giardino^¶, Guntram Suske^||, Naila Rabbani^**, Paul J. Thornalley^**, Vijay P. Sarthy, Hans-Peter Hammes, and Michael Brownlee²

From the Juvenile Diabetes Research Foundation International Center for Diabetic Complications Research, Albert Einstein College of Medicine, Bronx, New York 10461, Kimmel Cancer Center, Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, ^¶Department of Biomedical Sciences, University of Foggia, Via Pinto 1, 71100 Foggia, Italy, ^||Institut fuer Molekularbiologie und Tumorforschung, Philipps-Universitaet Marburg, Emil-Mankopff-Strasse 2, D-35037 Marburg, Germany, ^**Protein Damage and Systems Biology Research Group, Warwick Medical School and Systems Biology Centre, Clinical Sciences Research Institute, University of Warwick, Coventry CV2 2DX, United Kingdom, Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60093, and Fifth Medizinische Klinik-Theodor-Kutzer-Ulfer 1-3, University of Mannheim, 68167 Mannheim, Germany

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

Received for publication, June 7, 2007 , and in revised form, July 31, 2007.

^* This work was supported by grants from the National Institutes of Health and the Juvenile Diabetes Research Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 718-430-3636; Fax: 718-430-8570; E-mail: brownlee{at}aecom.yu.edu.

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