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  • Title: Liraglutide Attenuates Myocardial Ischemia/Reperfusion Injury Through the Inhibition of Necroptosis by Activating GLP-1R/PI3K/Akt Pathway.
    Author: Zhou G, Wu H, Yang J, Ye M, Liu D, Li Y, Zhang D, Zhang J, Yang Q, Liu Y.
    Journal: Cardiovasc Toxicol; 2023 Apr; 23(3-4):161-175. PubMed ID: 36934206.
    Abstract:
    Necroptosis is a crucial programmed cell death that is tightly associated with myocardial ischemia/reperfusion injury (MI/RI). Liraglutide is an effective option for the treatment of type 2 diabetes and has recently been reported to exert cardioprotective effects on MI/RI. Researchers do not know whether the cardioprotective effect of liraglutide is involved in regulating necroptosis. This study aimed to explore the effect of liraglutide on MI/RI-induced necroptosis and its potential mechanisms. Hypoxia/reoxygenation (H/R) was performed on H9c2 cells in vitro to simulate ischemia/reperfusion (I/R) injury, and an MI/RI rat model was established in vivo by ligating the anterior descending branch of the left coronary artery. H/R or I/R damage was assessed by performing biochemical assay, Hoechst 33342/PI staining, H&E (hematoxylin and eosin) staining, and Annexin-V/PI staining. Our data revealed that liraglutide resulted in markedly increased cell viability and reduced cardiac enzyme release by protecting cardiomyocytes from a necrosis-like phenotype after H/R. The myocardial infarct size and cardiac enzyme release were reduced in the heart tissues from the liraglutide-treated group. The levels of necroptosis-associated proteins (receptor-interacting protein kinase 3 (RIPK3), p-RIPK3, and phosphorylated-mixed lineage kinase domain-like protein (p-MLKL)) were also reduced by the liraglutide treatment. Mechanistically, we revealed that liraglutide exerted cardioprotective effects through a glucagon-like peptide-1 receptor (GLP-1R) and phosphatidylinositol-3 kinase (PI3K)-dependent pathway. Both the GLP-1R inhibitor exendin (9-39) and the PI3K inhibitor LY294002 abrogated the protective effects of liraglutide in vitro. We found that liraglutide may attenuate MI/RI by inhibiting necroptosis, in part by enhancing the activity of the GLP-1R/PI3K/Akt pathway.
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