Ferulic Acid Alleviates Myocardial Ischemia Reperfusion Injury Via Upregulating AMPK alpha 2 Expression-Mediated Ferroptosis Depression

Journal of cardiovascular pharmacology(2022)

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摘要
Ferroptosis, a recently discovered form of regulated cell death that is characterized by iron accumulation and excessive reactive oxygen species generation, has been favored by most researchers. Increasing evidence suggest that ferulic acid (FA) could exert marked effects to myocardial ischemia reperfusion (I/R) injury, although the understanding of its molecular mechanism is still limited. In our study, the myocardial PR injury model was established to explore the relationship between FR injury and ferroptosis. First, we successfully constructed myocardial PR injury model with changes in ST segment, increased creatine phosphokinase, lactate dehydrogenase activities, and N-Terminal Pro Brain Natriuretic Peptide content, and a significantly larger infarct size. Then, the increased levels of the Ptgs2 mRNA, Fe2+ accumulation, and a decreased reduced glutathione/oxidized glutathione disulfide ratio were detected in ischemia-reperfusion-injured heart, which is highly consistent with ferroptosis. However, these effects were significantly improved after FA treatment. Based on these results, FA increased the activities of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, decreased the malondialdehyde level, ameliorated the production of reactive oxygen species, and promoted the generation of adenosine triphosphate. These effects of FA are similar to those of the ferroptosis inhibitor ferrostatin-1. Upregulation of AMPK alpha 2 and Glutathione Peroxidase 4 expression were also observed in the FA group. Compound C, a specific Adenosine 5'-monophosphate (AMP)-activated protein kinase inhibitor, significantly blocked the protective effect of FA. These findings underlined that FA inhibits ferroptosis by upregulating the expression of AMPK alpha 2 and serves as a cardioprotective strategy.
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关键词
ferulic acid, myocardial ischemia reperfusion injury, AMPK alpha 2, ferroptosis
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