The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects
The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects
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DOI：
10.1152/ajpheart.00756.2008
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发表时间：
2009-03-01
影响因子：
4.8
通讯作者：
Yang, Zhihong
中科院分区：
文献类型：
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作者：
Rajapakse, Angana Gupta;Ming, Xiu-Fen;Yang, Zhihong
Rajapakse AG，Ming XF，Carvas JM，Yang Z.氨基己糖生物合成抑制剂阿扎司他丁通过抗氧化作用预防高血糖条件下的内皮炎症和功能障碍。Am J Physiol Heart Circ Physiol 296：H815-H822，2009。首次发表于2009年1月9日; doi：10.1152/ajpheart.00756.2008。己糖胺生物合成途径（HBP）解释了高血糖的一些心血管不良反应。我们研究了HBP抑制剂阿扎胞苷是否依赖于HBP而保护高血糖诱导的内皮损伤。将从脐静脉分离的人内皮细胞暴露于高浓度（30.5 mmol/l）或低浓度（5.5 mmol/l）葡萄糖4天，然后用TNF-α刺激（1 ng/ml，24 h）。阻断限速酶谷氨酰胺：果糖-6-磷酸酰胺转移酶可抑制高血糖条件下的HBP通量和氧化应激（产生超氧化物和过氧亚硝酸盐），并防止高血糖和TNF-α对VCAM-1和ICAM-1表达的协同刺激。在低葡萄糖条件下培养的细胞中，当HBP流量没有增加时，阿扎胞苷提高锰超氧化物歧化酶（MnSOD）蛋白水平，并抑制氧化应激和VCAM-1和ICAM-1的表达，以响应TNF-α。此外，多酚白藜芦醇抑制氧化应激和粘附分子的表达，并没有降低高血糖条件下的HBP流量。此外，在离体大鼠腹主动脉暴露于高血糖缓冲液5小时时，没有显着的HBP流量发生，阿扎胞苷上调MnSOD蛋白水平，并防止降低内皮依赖性舒张乙酰胆碱。总之，高血糖独立地增加氧化应激和HBP通量，放大内皮炎症，并主要通过氧化应激而不是HBP途径损害内皮功能。阿扎胞苷通过其独立于抑制HBP通路的抗氧化作用保护高血糖内皮损伤。
Rajapakse AG, Ming XF, Carvas JM, Yang Z. The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects. Am J Physiol Heart Circ Physiol 296: H815-H822, 2009. First published January 9, 2009; doi:10.1152/ajpheart.00756.2008.-Hexosamine biosynthetic pathway (HBP) accounts for some cardiovascular adverse effects of hyperglycemia. We investigated whether the HBP inhibitor azaserine protects against hyperglycemia-induced endothelial damage dependently of HBP. Human endothelial cells isolated from umbilical veins were exposed either to a high (30.5 mmol/l) or low concentration of glucose (5.5 mmol/l) for 4 days, followed by a stimulation with TNF-alpha (1 ng/ml, 24 h). The blockade of the rate-limiting enzyme glutamine:fructose-6-phosphate amidotransferase inhibited HBP flux and oxidative stress (generation of superoxide and peroxynitrite) under the hyperglycemic condition and prevented the synergistic stimulation of VCAM-1 and ICAM-1 expression by hyperglycemia and TNF-alpha. In the cells cultured under a low-glucose condition when no increased HBP flux occurred, azaserine enhanced the manganese-superoxide dismutase (MnSOD) protein level and also inhibited the oxidative stress and the expression of VCAM-1 and ICAM-1 in response to TNF-alpha. Moreover, the polyphenol resveratrol inhibited the oxidative stress and adhesion molecule expression and did not decrease the HBP flux under the hyperglycemia condition. In addition, in isolated rat aortas exposed to hyperglycemic buffer for 5 h when no significant HBP flux occurred, azaserine upregulated the MnSOD protein level and prevented decreased endothelium-dependent relaxations to acetylcholine. In conclusion, hyperglycemia independently increases oxidative stress and HBP flux, amplifies endothelial inflammation, and impairs endothelial function mainly through oxidative stress and not the HBP pathway. Azaserine protects against hyperglycemic endothelial damage through its antioxidant effect independently of inhibiting HBP pathway.