Isoliquiritigenin Ameliorates Ischemia-Induced Myocardial Injury via Modulating the Nrf2/HO-1 Pathway in Mice.
Isoliquiritigenin Ameliorates Ischemia-Induced Myocardial Injury via Modulating the Nrf2/HO-1 Pathway in Mice.
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DOI：
10.2147/dddt.s362754
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发表时间：
2022
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氧化应激和炎症反应在急性心肌梗死（AMI）中起着重要作用。异甘草素（Isoliquiritigenin，ISL）是一种从甘草中提取的黄酮类单体，在癌症研究中被发现具有抗氧化和抗炎作用。在此，我们在小鼠AMI模型中测试ISL对缺血诱导的心肌损伤的作用和潜在机制。成年C57 BL/6小鼠分别通过腹腔注射ISL和/或特异性核因子E2相关因子2（Nrf 2）抑制剂ML 385预处理3天。结扎左冠状动脉前降支分支建立急性心肌梗死模型。术后第7天评价心肌氧化应激状态、炎症反应、心功能和梗死面积。与假手术组比较，AMI组大鼠心肌组织中活性氧（ROS）和丙二醛（MDA）水平明显升高。超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）水平显著降低。ISL能明显缩小心肌梗死面积，改善心功能，抑制ROS和MDA的产生，减少SOD和GSH-Px的消耗。ISL可显著提高梗死心肌细胞核Nrf 2和胞浆血红素氧合酶1（HO-1）水平，减轻心肌梗死后的氧化应激。ISL能显著抑制AMI组心肌NF-κB通路的激活，降低促炎因子的表达。然而，ML 385的给药不仅抑制了ISL诱导的Nrf 2/HO-1活化、抗氧化和抗炎作用，而且减弱了ISL在减少AMI小鼠梗死面积和改善心功能方面的有益作用。结果提示，Nrf 2/HO-1通路的激活可能通过减轻心肌氧化应激和炎症反应，在缺血再灌注诱导的心肌保护中发挥重要作用。
Oxidative stress and inflammatory reaction play critical roles in acute myocardial infarction (AMI). Isoliquiritigenin (ISL), a flavonoid monomer extracted from licorice, has been found to have antioxidant and anti-inflammatory effects in cancer studies. Here, we tested the effect and underlying mechanisms of ISL on ischemia-induced myocardial injury in a mouse AMI model. Adult C57BL/6 mice were pre-treated by intraperitoneal injection of ISL and/or a specific nuclear factor E2-related factor 2 (Nrf2) inhibitor ML385 for 3 days, respectively. Then, the AMI model was established by ligating the anterior descending branch of the left coronary artery. Myocardial oxidative stress status, inflammatory response, cardiac function and infarction size were assessed after 7th day of surgery. Compared with sham group, the reactive oxygen species (ROS) and malondialdehyde (MDA) level in AMI group were significantly increased. However, the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) level were dramatically decreased. ISL treatment significantly reduced the myocardial infarction area, improved cardiac function, inhibited the production of ROS and MDA and reduced the consumption of SOD and GSH-Px. Interestingly, ISL could significantly increase nuclear Nrf2 and cytosolic heme oxygenase 1 (HO-1) level in the infarcted myocardium and reduce the oxidative stress after AMI. Also, ISL treatment dramatically inhibited the activation of myocardial NF-κB pathway and reduced the expression of pro-inflammatory factors in the AMI group. However, the administration of ML385 not only suppressed the Nrf2/HO-1 activation, the anti-oxidant and anti-inflammatory effects induced by ISL, but also attenuated the beneficial role of ISL on reducing infarct size and improving cardiac function in the mouse with AMI. The results suggested that activation of Nrf2/HO-1 pathway has an essential role in ISL-induced cardiac protection by alleviating myocardial oxidative stress and inflammation response in mice with AMI.