High Glucose Increases Angiopoietin-2 Transcription in Microvascular Endothelial Cells through Methylglyoxal Modification of mSin3A*
High Glucose Increases Angiopoietin-2 Transcription in Microvascular Endothelial Cells through Methylglyoxal Modification of mSin3A*
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DOI：
10.1074/jbc.m704703200
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发表时间：
2007-10
影响因子：
4.8
通讯作者：
Dachun Yao;T. Taguchi;T. Matsumura;R. Pestell;D. Edelstein;I. Giardino;G. Suske;N. Rabbani;Paul J Thornalley;V. Sarthy;H. Hammes;M. Brownlee
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文献类型：
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作者：
Dachun Yao;T. Taguchi;T. Matsumura;R. Pestell;D. Edelstein;I. Giardino;G. Suske;N. Rabbani;Paul J Thornalley;V. Sarthy;H. Hammes;M. Brownlee
甲基乙二醛是糖酵解过程中由磷酸丙糖形成的高反应性二羰基降解产物。甲基乙二醛主要与细胞内蛋白质的精氨酸残基形成稳定的加合物。这种共价修饰在调节细胞功能中的生物学作用尚不清楚。在这里，我们报告在小鼠肾内皮细胞中，高葡萄糖导致辅阻遏物 mSin3A 的甲基乙二醛修饰增加。 mSin3A 的甲基乙二醛修饰导致 O-GlcNAc 转移酶的募集增加，从而增加了 O-连接的 N-乙酰氨基葡萄糖对 Sp3 的修饰。 Sp3 的这种修饰导致血管生成素 2 (Ang-2) 启动子中与葡萄糖响应性 GC 盒的结合减少，从而导致 Ang-2 表达增加。高葡萄糖诱导的 Ang-2 表达增加会增加糖尿病小鼠细胞和肾脏中细胞内粘附分子 1 和血管细胞粘附分子 1 的表达，并使微血管内皮细胞对肿瘤坏死因子 α 的促炎作用敏感。这种调节基因表达的新机制可能在糖尿病血管疾病的病理学中发挥作用。
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 α. This novel mechanism for regulating gene expression may play a role in the pathobiology of diabetic vascular disease.