Isoliquiritigenin Ameliorates Ischemia-Induced Myocardial Injury via Modulating the Nrf2/HO-1 Pathway in Mice

Deshan Yao,1,2 Bo Shi,3 Sichuan Wang,1,2 Liuxiang Bao,1,2 Meng Tan,1,2 Hui Shen,1,2 Zhengang Zhang,1,2 Xin Pan,1,2 Yi Yang,1,2 Yong Wu,1,2 Kaizheng Gong1,2 1Department of Cardiology, the Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, 225001, People’s Republic of China; 2Jiangsu Key Laboratory of Integrative Medicine for the Control of Geriatrics and Institute of Cardiovascular Disease, Yangzhou University, Yangzhou, 225001, People’s Republic of China; 3School of Life Science, Liaoning Normal University, Dalian, 116081, People’s Republic of ChinaCorrespondence: Kaizheng Gong; Yong Wu, Department of Cardiology, the Affiliated Hospital of Yangzhou University, Yangzhou University, No. 368 Hanjiang Middle Road, Yangzhou, 225001, People’s Republic of China, Tel +86-514-82981199, Email yungkzh@163.com; 154629676@qq.comBackground: 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.Methods: 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.Results: 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.Conclusion: 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.Keywords: isoliquiritigenin, acute myocardial infarction, oxidative stress, Nrf2, NF-κB