Luteolin Attenuates Cardiac Ischemia/Reperfusion Injury in Diabetic Rats by Modulating Nrf2 Antioxidative Function
Luteolin Attenuates Cardiac Ischemia/Reperfusion Injury in Diabetic Rats by Modulating Nrf2 Antioxidative Function
复制标题
木犀草素通过调节 Nrf2 抗氧化功能减轻糖尿病大鼠的心脏缺血/再灌注损伤
DOI：
10.1155/2019/2719252
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发表时间：
2019-01-01
影响因子：
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通讯作者：
Qian, Ling-Bo
中科院分区：
文献类型：
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作者：
Xiao, Chi;Xia, Man-Li;Qian, Ling-Bo
据报道，木犀草素通过内皮型一氧化氮合酶（eNOS）相关的抗氧化反应，减轻糖尿病心脏缺血/再灌注（I/R）损伤。虽然核因子红细胞2相关因子2 （Nrf2）被认为是降低糖尿病氧化应激的关键内源性因子，但木犀草素是否通过增强Nrf2功能来减轻糖尿病心脏I/R损伤尚不清楚。我们假设木犀草素预处理可以通过影响eNOS/Nrf2信号通路减轻糖尿病心脏I/R损伤。先给糖尿病大鼠单次注射链脲佐菌素（65 mg/kg, ig） 6周，再给木犀草素（100 mg/kg/天，ig）、eNOS抑制剂L-NAME或Nrf2抑制剂brusatol 2周。然后，对离体大鼠心脏进行30min的全脑缺血和120min的再灌注，建立I/R损伤。木犀草素显著改善心功能和心肌活力；血红素氧化酶-1、超氧化物歧化酶、谷胱甘肽过氧化物酶和过氧化氢酶表达上调；降低心肌乳酸脱氢酶释放、丙二醛和8-羟基脱氧鸟苷在糖尿病I/R心脏中的含量。木犀草素的这些改善作用被L-NAME或brusatol显著逆转。木犀草素还显著降低kelch样ECH-associated protein 1 （Keap1）的s -亚硝基化，上调Nrf2及其转录活性。木犀草素对Keap1/Nrf2信号通路的影响被L-NAME减弱。这些数据表明木犀草素通过增强enos介导的Keap1的s -亚硝基化，随后上调Nrf2和Nrf2相关的抗氧化信号通路，从而保护糖尿病心脏免受I/R损伤。
Luteolin has been reported to attenuate ischemia/reperfusion (I/R) injury in the diabetic heart through endothelial nitric oxide synthase- (eNOS-) related antioxidative response. Though the nuclear factor erythroid 2-related factor 2 (Nrf2) is regarded as a key endogenous factor to reduce diabetic oxidative stress, whether luteolin reduces cardiac I/R injury in the diabetic heart via enhancing Nrf2 function needs to be clarified. We hypothesized that pretreatment with luteolin could alleviate cardiac I/R injury in the diabetic heart by affecting the eNOS/Nrf2 signaling pathway. The diabetic rat was produced by a single injection of streptozotocin (65 mg/kg, i.p.) for 6 weeks, and then, luteolin (100 mg/kg/day, i.g.), eNOS inhibitor L-NAME, or Nrf2 inhibitor brusatol was administered for the succedent 2 weeks. After that, the isolated rat heart was exposed to 30 min of global ischemia and 120 min of reperfusion to establish I/R injury. Luteolin markedly ameliorated cardiac function and myocardial viability; upregulated expressions of heme oxygenase-1, superoxide dismutase, glutathione peroxidase, and catalase; and reduced myocardial lactate dehydrogenase release, malondialdehyde, and 8-hydroxydeoxyguanosine in the diabetic I/R heart. All these ameliorating effects of luteolin were significantly reversed by L-NAME or brusatol. Luteolin also markedly reduced S-nitrosylation of Kelch-like ECH-associated protein 1 (Keap1) and upregulated Nrf2 and its transcriptional activity. This effect of luteolin on Keap1/Nrf2 signaling was attenuated by L-NAME. These data reveal that luteolin protects the diabetic heart against I/R injury by enhancing eNOS-mediated S-nitrosylation of Keap1, with subsequent upregulation of Nrf2 and the Nrf2-related antioxidative signaling pathway.