Department of Pharmacology, College of Medicine, University of Saskatchewan, A120 Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, Canada S7N 5E5.
Cardiovasc Res. 2011 Dec 1;92(3):494-503. doi: 10.1093/cvr/cvr239. Epub 2011 Sep 2.
Methylglyoxal (MG) overproduction has been reported in metabolic syndrome with hyperglycaemia (diabetes) or without hyperglycaemia (hypertension), and the underlying mechanism was investigated.
Contributions of different pathways or enzymes to MG formation were evaluated in aorta or cultured vascular smooth muscle cells (VSMCs). In all four animal models of metabolic syndrome, i.e. chronically fructose-fed hypertensive Sprague-Dawley rats, spontaneously hypertensive rats, obese non-diabetic Zucker rats, and diabetic Zucker rats, serum and aortic MG and fructose levels were increased, and the expression of GLUT5 (transporting fructose) and aldolase B (converting fructose to MG) in aorta were up-regulated. Aortic expressions of aldolase A, semicarbazide-sensitive amine oxidase (SSAO), and cytochrome P450 2E1 (CYP 2E1), accounting for MG formation during glycolysis, protein, and lipid metabolism, respectively, was unchanged/reduced. Fructose (25 mM) treatment of VSMCs up-regulated the expression of GLUT5 and aldolase B and accelerated MG formation. Insulin (100 nM) increased GLUT5 expression and augmented fructose-increased cellular fructose accumulation and MG formation. Glucose (25 mM) treatment activated the polyol pathway and enhanced fructose formation, leading to aldolase B upregulation and MG overproduction. Inhibition of the polyol pathway reduced the glucose-increased aldolase B expression and MG generation. The excess formation of MG in under these conditions was eliminated by knock-down of aldolase B, but not by knock-down of aldolase A or inhibition of SSAO or CYP 2E1.
Upregulation of aldolase B by accumulated fructose is a common mechanism for MG overproduction in VSMCs and aorta in different models of metabolic syndrome.
已有研究报道，在伴有高血糖（糖尿病）或不伴有高血糖（高血压）的代谢综合征中，甲基乙二醛（MG）的产量增加，本研究旨在探讨其潜在机制。
在主动脉或培养的血管平滑肌细胞（VSMC）中，评估了不同途径或酶对 MG 形成的贡献。在代谢综合征的所有四种动物模型中，即慢性果糖喂养的高血压 Sprague-Dawley 大鼠、自发性高血压大鼠、肥胖非糖尿病 Zucker 大鼠和糖尿病 Zucker 大鼠中，血清和主动脉中的 MG 和果糖水平升高，并且主动脉中 GLUT5（转运果糖）和醛缩酶 B（将果糖转化为 MG）的表达上调。主动脉中分别负责糖酵解、蛋白质和脂质代谢中 MG 形成的醛缩酶 A、氨基乙内酰脲敏感胺氧化酶（SSAO）和细胞色素 P450 2E1（CYP 2E1）的表达保持不变/减少。果糖（25mM）处理 VSMC 可上调 GLUT5 和醛缩酶 B 的表达并加速 MG 形成。胰岛素（100nM）增加 GLUT5 的表达，并增强果糖增加的细胞果糖积累和 MG 形成。葡萄糖（25mM）处理激活多元醇途径并增强果糖形成，导致醛缩酶 B 上调和 MG 过量产生。多元醇途径的抑制减少了葡萄糖增加的醛缩酶 B 表达和 MG 的产生。在这些条件下，通过敲低醛缩酶 B 消除了 MG 的过量产生，但通过敲低醛缩酶 A 或抑制 SSAO 或 CYP 2E1 则不能消除。
在不同代谢综合征模型的 VSMC 和主动脉中，积累的果糖上调醛缩酶 B 是 MG 过量产生的共同机制。
