AUTHOR=Zhang Min , Wei Li , Xie Saiyang , Xing Yun , Shi Wenke , Zeng Xiaofeng , Chen Si , Wang Shasha , Deng Wei , Tang Qizhu 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.794982

DOI=10.3389/fphar.2021.794982

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> As a plant-derived polycyclic phenolic carboxylic acid isolated from <italic>Salvia miltiorrhiza</italic>, 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.</p><p><bold>Methods:</bold> 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 <italic>in vitro</italic> 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<italic>α</italic>/Nrf2 in LA-mediated effects.</p><p><bold>Results:</bold> 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 <italic>in vivo and in vitro</italic>. In terms of mechanism, LA selectively activates eNOS, simultaneously increases nuclear translocation and phosphorylation of Nrf2 and promotes Nrf2/HO-1 pathway <italic>in vivo and in vitro</italic>, while cardioprotection of LA is abolished by pharmacological inhibitor of AMPK or Nrf2 siRNA in H9C2 cells.</p><p><bold>Conclusion:</bold> LA protects against MI/R-induced cardiac injury by promoting eNOS and Nrf2/HO-1 signaling via phosphorylation of AMPK<italic>α</italic>.</p>