High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A.
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.
Juvenile Diabetes Research Foundation International Center for Diabetic Complications Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Dachun
D
Yao
Tetsuya
T
Taguchi
Takeshi
T
Matsumura
Richard
R
Pestell
Diane
D
Edelstein
Ida
I
Giardino
Guntram
G
Suske
Naila
N
Rabbani
Paul J
PJ
Thornalley
Vijay P
VP
Sarthy
Hans-Peter
HP
Hammes
Michael
M
Brownlee
D000117:Acetylglucosamine / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D011765:Pyruvaldehyde / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D051705:Sp3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013549:Sweetening Agents / Q000378:metabolism / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D042702:Angiopoietin-2; D012097:Repressor Proteins; C099683:SIN3A transcription factor; C497122:Sp3 protein, mouse; D013549:Sweetening Agents; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D051705:Sp3 Transcription Factor; D011765:Pyruvaldehyde; D001120:Arginine; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D005947:Glucose; D000117:Acetylglucosamine