Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose
Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose
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DOI：
10.1111/j.1476-5381.2010.01017.x
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发表时间：
2010-12-01
影响因子：
7.3
通讯作者：
Wu, Lingyun
中科院分区：
文献类型：
--
作者：
Dhar, Arti;Dhar, Indu;Wu, Lingyun
背景与目的内皮功能障碍是高血压和糖尿病的一个特征。甲基乙二醛（MG）是葡萄糖的活性二羰基代谢物，其水平在自发性高血压大鼠和糖尿病患者中升高。我们研究了MG是否会诱导内皮功能障碍，以及MG清除剂是否能预防MG和高葡萄糖浓度诱导的内皮功能障碍。实验方法研究了Sprague-Dawley大鼠主动脉环内皮依赖性松弛。我们还使用了培养的大鼠主动脉和人脐静脉内皮细胞。采用高效液相色谱法和Western blotting法测定MG含量。关键结果：MG （30 μ M）或高糖（25 μ M）对主动脉环的培养可减弱内皮依赖性乙酰胆碱诱导的松弛，而两种不同的MG清除剂氨基胍（100 μ M）和n -乙酰半胱氨酸（600 μ M）可恢复内皮依赖性乙酰胆碱诱导的松弛。用MG或高糖处理培养的内皮细胞可增加细胞MG水平，氨基胍和NAC可阻止这种作用。在培养的内皮细胞中，MG和高葡萄糖降低了基底和缓激肽刺激的一氧化氮（NO）生成、cGMP水平、丝氨酸-1177磷酸化和内皮NO合成酶（eNOS）活性，而不影响苏氨酸-495和Akt磷酸化或eNOS总蛋白。MG和高糖的这些作用被氨基胍或NAC减弱。研究结果首次表明，MG降低了丝氨酸-1177磷酸化、eNOS活性和NO生成。MG引起的内皮功能障碍与高糖引起的内皮功能障碍相似。特异性和安全的MG清除剂有可能预防由MG和高葡萄糖浓度引起的内皮功能障碍。
BACKGROUND AND PURPOSEEndothelial dysfunction is a feature of hypertension and diabetes. Methylglyoxal (MG) is a reactive dicarbonyl metabolite of glucose and its levels are elevated in spontaneously hypertensive rats and in diabetic patients. We investigated if MG induces endothelial dysfunction and whether MG scavengers can prevent endothelial dysfunction induced by MG and high glucose concentrations.EXPERIMENTAL APPROACHEndothelium-dependent relaxation was studied in aortic rings from Sprague-Dawley rats. We also used cultured rat aortic and human umbilical vein endothelial cells. The MG was measured by HPLC and Western blotting and assay kits were used.KEY RESULTSIncubation of aortic rings with MG (30 mu M) or high glucose (25 mM) attenuated endothelium-dependent, acetylcholine-induced relaxation, which was restored by two different MG scavengers, aminoguanidine (100 mu M) and N-acetyl cysteine (NAC) (600 mu M). Treatment of cultured endothelial cells with MG or high glucose increased cellular MG levels, effects prevented by aminoguanidine and NAC. In cultured endothelial cells, MG and high glucose reduced basal and bradykinin-stimulated nitric oxide (NO) production, cGMP levels, and serine-1177 phosphorylation and activity of endothelial NO synthase (eNOS), without affecting threonine-495 and Akt phosphorylation or total eNOS protein. These effects of MG and high glucose were attenuated by aminoguanidine or NAC.CONCLUSIONS AND IMPLICATIONSOur results show for the first time that MG reduced serine-1177 phosphorylation, activity of eNOS and NO production. MG caused endothelial dysfunction similar to that induced by high glucose. Specific and safe MG scavengers have potential to prevent endothelial dysfunction induced by MG and high glucose concentrations.