Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury from Oxidative Stress by Regulating Succinate, Lysophospholipid Metabolism, and ROS Scavenging System
Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury from Oxidative Stress by Regulating Succinate, Lysophospholipid Metabolism, and ROS Scavenging System
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DOI：
10.1155/2019/9137654
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发表时间：
2019-01-01
影响因子：
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通讯作者：
Fan, Guanwei
中科院分区：
文献类型：
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作者：
Jiang, Miaomiao;Ni, Jingyu;Fan, Guanwei
黄芪甲苷是从黄芪中分离得到的主要活性成分之一。在此，我们证实了其对心肌缺血再灌注损伤的保护作用，并旨在探讨其潜在的分子机制。黄芪甲苷对体外和体内I/R模型大鼠的心肌梗死面积、收缩和舒张期功能障碍的比例以及肌酸激酶和乳酸脱氢酶的产生均有明显的抑制作用。代谢分析表明，I/R损伤后琥珀酸显著降低，溶血磷脂显著升高，提示琥珀酸的快速再氧化和甘油磷脂的降解导致了过量的ROS生成。分子机制验证表明，黄芪皂苷IV刺激Kelch样ECH相关蛋白1(Keap1)释放的核因子(红系衍生2)样2(Nrf2)转位到细胞核，与肌肉腱膜纤维肉瘤(Maf)结合，启动抗氧化基因血红素加氧酶-1(HO-1)的转录，在心脏中执行广泛的ROS清除过程，对抗病理性氧化应激。不出所料，与I/R模型组相比，黄芪甲苷IV预处理组琥珀酸含量增加，溶血磷脂含量降低。提示黄芪甲苷通过调节琥珀酸和溶血磷脂代谢，通过Nrf2信号通路清除ROS，从而减轻心肌I/R损伤。
Astragaloside IV is one of the main active ingredients isolated from Astragalus membranaceus. Here we confirmed its protective effect against cardiac ischemia-reperfusion (I/R) injury and aimed to investigate the potential molecular mechanisms involved. Pretreatment of ex vivo and in vivo I/R-induced rat models by astragaloside IV significantly prevented the ratio of myocardium infarct size, systolic and diastolic dysfunction, and the production of creatine kinase and lactate dehydrogenase. Metabolic analyses showed that I/R injury caused a notable reduction of succinate and elevation of lysophospholipids, indicating excessive reactive oxygen species (ROS) generation driven by succinate's rapid reoxidization and glycerophospholipid degradation. Molecular validation mechanistically revealed that astragaloside IV stimulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) released from Kelch-like ECH-associated protein 1 (Keap1) and translocated to the nucleus to combine with musculoaponeurotic fibrosarcoma (Maf) to initiate the transcription of antioxidative gene heme oxygenase-1 (HO-1), which performed a wide range of ROS scavenging processes against pathological oxidative stress in the hearts. As expected, increasing succinate and decreasing lysophospholipid levels were observed in the astragaloside IV-pretreated group compared with the I/R model group. These results suggested that astragaloside IV ameliorated myocardial I/R injury by modulating succinate and lysophospholipid metabolism and scavenging ROS via the Nrf2 signal pathway.