Diabetes and Obesity Center, University of Louisville, Louisville, Kentucky, USA.
Diabetes. 2009 Nov;58(11):2486-97. doi: 10.2337/db09-0375. Epub 2009 Aug 3.
To examine the role of aldo-keto reductases (AKRs) in the cardiovascular metabolism of the precursors of advanced glycation end products (AGEs).
Steady-state kinetic parameters of AKRs with AGE precursors were determined using recombinant proteins expressed in bacteria. Metabolism of methylglyoxal and AGE accumulation were studied in human umbilical vein endothelial cells (HUVECs) and C57 wild-type, akr1b3 (aldose reductase)-null, cardiospecific-akr1b4 (rat aldose reductase), and akr1b8 (FR-1)-transgenic mice. AGE accumulation and atherosclerotic lesions were studied 12 weeks after streptozotocin treatment of C57, akr1b3-null, and apoE- and akr1b3-apoE-null mice.
Higher levels of AGEs were generated in the cytosol than at the external surface of HUVECs cultured in high glucose, indicating that intracellular metabolism may be an important regulator of AGE accumulation and toxicity. In vitro, AKR 1A and 1B catalyzed the reduction of AGE precursors, whereas AKR1C, AKR6, and AKR7 were relatively ineffective. Highest catalytic efficiency was observed with AKR1B1. Acetol formation in methylglyoxal-treated HUVECs was prevented by the aldose reductase inhibitor sorbinil. Acetol was generated in hearts perfused with methylglyoxal, and its formation was increased in akr1b4- or akr1b8-transgenic mice. Reduction of AGE precursors was diminished in hearts from akr1b3-null mice. Diabetic akr1b3-null mice accumulated more AGEs in the plasma and the heart than wild-type mice, and deletion of akr1b3 increased AGE accumulation and atherosclerotic lesion formation in apoE-null mice.
Aldose reductase-catalyzed reduction is an important pathway in the endothelial and cardiac metabolism of AGE precursors, and it prevents AGE accumulation and atherosclerotic lesion formation.
研究醛酮还原酶（AKR）在晚期糖基化终产物（AGE）前体的心血管代谢中的作用。
使用在细菌中表达的重组蛋白测定 AKR 与 AGE 前体的稳态动力学参数。在人脐静脉内皮细胞（HUVEC）和 C57 野生型、akr1b3（醛糖还原酶）缺失、心脏特异性-akr1b4（大鼠醛糖还原酶）和 akr1b8（FR-1）转基因小鼠中研究了甲基乙二醛和 AGE 积累的代谢。在链脲佐菌素处理的 C57、akr1b3 缺失和 apoE-和 akr1b3-apoE 缺失小鼠中，研究了 12 周后的 AGE 积累和动脉粥样硬化病变。
在高葡萄糖培养的 HUVEC 细胞的细胞溶胶中生成的 AGE 水平高于细胞外表面，表明细胞内代谢可能是 AGE 积累和毒性的重要调节剂。在体外，AKR1A 和 1B 催化 AGE 前体的还原，而 AKR1C、AKR6 和 AKR7 的作用相对较弱。观察到 AKR1B1 的最高催化效率。在甲基乙二醛处理的 HUVEC 中，醛糖还原酶抑制剂 sorbinil 可防止乙缩醛的形成。在灌注甲基乙二醛的心脏中生成了乙缩醛，并且在 akr1b4 或 akr1b8 转基因小鼠中其形成增加。akr1b3 缺失的心脏中 AGE 前体的还原减少。与野生型小鼠相比，糖尿病 akr1b3 缺失小鼠的血浆和心脏中 AGEs 积累更多，并且 akr1b3 的缺失增加了 apoE 缺失小鼠的 AGE 积累和动脉粥样硬化病变形成。
醛糖还原酶催化的还原是内皮细胞和心脏 AGE 前体代谢的重要途径，可防止 AGE 积累和动脉粥样硬化病变形成。
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