Reductive metabolism of AGE precursors: a metabolic route for preventing AGE accumulation in cardiovascular tissue.
Reductive metabolism of AGE precursors: a metabolic route for preventing AGE accumulation in cardiovascular tissue.
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DOI：
10.2337/db09-0375
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发表时间：
2009-11
期刊：
影响因子：
7.7
通讯作者：
Srivastava S
中科院分区：
文献类型：
--
作者：
Baba SP;Barski OA;Ahmed Y;O'Toole TE;Conklin DJ;Bhatnagar A;Srivastava S
研究醛酮还原酶 (AKR) 在晚期糖基化终末产物 (AGE) 前体的心血管代谢中的作用。使用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）无效、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。在链脲佐菌素治疗 C57、akr1b3-null、apoE-和 akr1b3-apoE-null 小鼠后 12 周，研究了 AGE 积累和动脉粥样硬化病变。在高葡萄糖条件下培养的 HUVEC 细胞质中产生的 AGE 水平高于外表面，表明细胞内代谢可能是 AGE 积累和毒性的重要调节因子。在体外，AKR 1A 和 1B 催化 AGE 前体的还原，而 AKR1C、AKR6 和 AKR7 相对无效。 AKR1B1 的催化效率最高。醛糖还原酶抑制剂索宾尼尔可防止经甲基乙二醛处理的 HUVEC 中丙酮醇的形成。丙酮醇在灌注甲基乙二醛的心脏中产生，并且在 akr1b4 或 akr1b8 转基因小鼠中其形成增加。 akr1b3 缺失小鼠心脏中 AGE 前体的减少减少。与野生型小鼠相比，akr1b3缺失的糖尿病小鼠在血浆和心脏中积累了更多的AGE，并且akr1b3缺失增加了apoE缺失小鼠中AGE的积累和动脉粥样硬化病变的形成。醛糖还原酶催化的还原是 AGE 前体的内皮和心脏代谢的重要途径，它可以防止 AGE 积累和动脉粥样硬化病变形成。
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.
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影响因子：
3.5
作者：
Schalkwijk, CG;van Bezu, J;van Hinsbergh, VWM
通讯作者：
van Hinsbergh, VWM
影响因子：
6
作者：
Goova, MT;Li, J;Schmidt, AM
通讯作者：
Schmidt, AM
影响因子：
15.9
作者：
SCHMIDT, AM;HORI, O;STERN, D
通讯作者：
STERN, D
DOI：
10.1006/bbrc.1996.1695
发表时间：
1996-11-12
影响因子：
3.1
作者：
Hamada, Y;Araki, N;Hotta, N
通讯作者：
Hotta, N
影响因子：
4.8
作者：
Ramana, Kota V.;Tammali, Ravinder;Srivastava, Satish K.
通讯作者：
Srivastava, Satish K.