Activation of Nrf2 by Lithospermic Acid Ameliorates Myocardial Ischemia and Reperfusion Injury by Promoting Phosphorylation of AMP-Activated Protein Kinase α (AMPK α )

• Published in: Frontiers in pharmacology 2021-11, Vol.12, p.794982-794982
• Main Authors: Zhang, Min, Wei, Li, Xie, Saiyang, Xing, Yun, Shi, Wenke, Zeng, Xiaofeng, Chen, Si, Wang, Shasha, Deng, Wei, Tang, Qizhu
• Format: Article
• Language: English
• Subjects: ampkα; lithospermic acid; myocardial ischemia-reperfusion injury (MIRI); Nrf2; oxidative stress; Pharmacology
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2021.794982

As a plant-derived polycyclic phenolic carboxylic acid isolated from , lithospermic acid (LA) has been identified as the pharmacological management for neuroprotection and hepatoprotection. However, the role and mechanism of lithospermic acid in the pathological process of myocardial ischemia-reperfusion injury are not fully revealed. C57BL/6 mice were subjected to myocardial ischemia and reperfusion (MI/R) surgery and pretreated by LA (50 mg/kg, oral gavage) for six consecutive days before operation. The model of hypoxia reoxygenation (HR) was induced by hypoxia for 24 h and reoxygenation for 6 h in H9C2 cells, which were subsequently administrated with lithospermic acid (100 μM). Nrf2 siRNA and dorsomorphin (DM), an inhibitor of AMPKα, were used to explore the function of AMPK /Nrf2 in LA-mediated effects. LA pretreatment attenuates infarct area and decreases levels of TnT and CK-MB in plasm following MI/R surgery in mice. Echocardiography and hemodynamics indicate that LA suppresses MI/R-induced cardiac dysfunction. Moreover, LA ameliorates oxidative stress and cardiomyocytes apoptosis following MI/R operation or HR . In terms of mechanism, LA selectively activates eNOS, simultaneously increases nuclear translocation and phosphorylation of Nrf2 and promotes Nrf2/HO-1 pathway , while cardioprotection of LA is abolished by pharmacological inhibitor of AMPK or Nrf2 siRNA in H9C2 cells. LA protects against MI/R-induced cardiac injury by promoting eNOS and Nrf2/HO-1 signaling via phosphorylation of AMPK .