Advanced Glycation End Products Accelerate Ischemia/Reperfusion Injury Through Receptor of Advanced End Product/Nitrative Thioredoxin Inactivation in Cardiac Microvascular Endothelial Cells
Advanced Glycation End Products Accelerate Ischemia/Reperfusion Injury Through Receptor of Advanced End Product/Nitrative Thioredoxin Inactivation in Cardiac Microvascular Endothelial Cells
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DOI：
10.1089/ars.2010.3764
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发表时间：
2011-10-01
影响因子：
6.6
通讯作者：
Tao, Ling
中科院分区：
文献类型：
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作者：
Liu, Yi;Ma, Yanzhuo;Tao, Ling
晚期糖基化终产物（AGEs）与心脏内皮损伤增加有关。然而，没有因果关系之间的联系已经建立增加AGEs和增强缺血/再灌注后的内皮损伤。更重要的是，AGEs可能增加内皮损伤的分子机制仍然未知。分离成年大鼠心脏微血管内皮细胞（CMECs），并与AGE修饰的牛血清白蛋白（BSA）或BSA孵育。AGE-BSA或BSA预培养后，对CMECs进行模拟缺血（SI）/再灌注（R）。AGE-BSA增加SI/R损伤，表现为乳酸脱氢酶释放和caspase-3活性增加。此外，AGE-BSA显着增加SI/R诱导的氧化/硝化应激CMECs（如增加诱导型一氧化氮合酶的表达，总一氧化氮的生产，超氧化物的产生，和过氧亚硝酸盐的形成）和增加SI/R诱导的硝化失活的硫氧还蛋白-1（Trx-1），一个重要的细胞保护分子。在AGE-BSA预培养的细胞中补充EUK 134（过氧亚硝酸盐分解催化剂）、人Trx-1或晚期终产物（sNAR）的可溶性受体（sNAR）（一种抗氧化剂诱饵）可减弱SI/R诱导的氧化/硝化应激，减少SI/R诱导的Trx-1硝化，保留Trx-1活性，并减少SI/R损伤。我们的研究结果表明，AGEs可能会增加SI/R诱导的内皮损伤，增加氧化/硝化损伤和随后的硝化失活的Trx-1。阻断TRX信号传导或恢复Trx活性的干预措施可能是减轻糖尿病患者内皮缺血/再灌注损伤的新疗法。抗氧化剂。氧化还原信号。15，1769-1778。
The advanced glycation end products (AGEs) are associated with increased cardiac endothelial injury. However, no causative link has been established between increased AGEs and enhanced endothelial injury after ischemia/reperfusion. More importantly, the molecular mechanisms by which AGEs may increase endothelial injury remain unknown. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and incubated with AGE-modified bovine serum albumin (BSA) or BSA. After AGE-BSA or BSA preculture, CMECs were subjected to simulated ischemia (SI)/reperfusion (R). AGE-BSA increased SI/R injury as evidenced by enhanced lactate dehydrogenase release and caspase-3 activity. Moreover, AGE-BSA significantly increased SI/R-induced oxidative/nitrative stress in CMECs (as measured by increased inducible nitric oxide synthase expression, total nitric oxide production, superoxide generation, and peroxynitrite formation) and increased SI/R-induced nitrative inactivation of thioredoxin-1 (Trx-1), an essential cytoprotective molecule. Supplementation of EUK134 (peroxynitrite decomposition catalyst), human Trx-1, or soluble receptor of advanced end product (sRAGE) (a RAGE decoy) in AGE-BSA precultured cells attenuated SI/R-induced oxidative/nitrative stress, reduced SI/R-induced Trx-1 nitration, preserved Trx-1 activity, and reduced SI/R injury. Our results demonstrated that AGEs may increase SI/R-induced endothelial injury by increasing oxidative/nitrative injury and subsequent nitrative inactivation of Trx-1. Interventions blocking RAGE signaling or restoring Trx activity may be novel therapies to mitigate endothelial ischemia/reperfusion injury in the diabetic population. Antioxid. Redox Signal. 15, 1769-1778.