Evaluating the Underlying Mechanisms of Bmal1/AKT/P53 Signaling Pathway-mediated Cardiomyocyte Ferroptosis and Oxidative Stress in Acute Myocardial Infarction

Abstract

Background: Acute myocardial infarction (AMI) is a cardiovascular disease induced by acute or persistent hypoxia in cardiomyocytes, resulting in irreversible damage to the heart. Therefore, we aimed to elucidate the role and mechanism of the Brain and muscle Arnt-like protein-1 (Bmal1)/AKT/P53 signaling pathway in mediating cardiomyocyte ferroptosis, oxidative stress, and inflammatory response in AMI. Methods: This study utilized H9C2 cardiomyocytes for hypoxia culture to establish an in vitro AMI model. Quantitative polymerase chain reaction (qPCR), Western blot analysis, and Enzyme-Linked Immunosorbent Assay (ELISA) assays were used to assess the expression levels of Bmal1/AKT/P53 signaling pathway-related molecules, Bmal1, p-AKT, and P53, along with other expression levels of associated factors within cardiomyocytes. Results: We observed that cardiomyocyte hypoxia promoted cardiomyocyte reactive oxygen species (ROS) production through the Bmal1/AKT/P53 signaling pathway. Furthermore, the expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly increased (p < 0.01), whereas glutathione peroxidase 4 (GPX4) and solute carrier family 7a member 11 (SLC7A11) were significantly decreased. Additionally, the inflammatory response-related factors, including interleukin-1α (IL-1α), IL-1β, IL-2, IL-6, Transforming growth factor β (TGF-β), and TGF-α were significantly increased (p < 0.01). Conclusion: This study explored that overexpression of Bmal1 activates AKT phosphorylation and inhibits oxidative stress, ferroptosis, and inflammation caused by cardiomyocyte hypoxia, thereby alleviating acute myocardial infarction.