Diosmetin improves myocardial ischemia/reperfusion injury via activation of the SIRT1/NRF2 axis.

Abstract

PURPOSE: Myocardial ischemia/reperfusion (I/R) injury is a potential complication associated with ischemic heart disease after recanalization. Diosmetin (Dios) is a natural flavonoid found in citrus species with therapeutic effects on several cardiovascular conditions. This study aims to explore the protective effects and mechanisms of Dios on myocardial I/R injury. METHODS: H9c2 cells were incubated with hydrogen peroxide (HO) in vitro to establish a cell model. An in vivo murine model of myocardial I/R injury was also established. The H9c2 cells or mice were exposed to Dios in the presence or absence of silent information regulator 1 (SIRT1) small interfering RNA (siRNA) or the selective SIRT1 inhibitor EX527. Immunoblotting, DHE staining, immunofluorescence, comet assay, Evans blue/TTC staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, enzyme-linked immunosorbent (ELISA) assay, and cell counting kit-8 (CCK-8) assay were performed. RESULTS: Dios treatment reduced HO-induced reactive oxygen species (ROS) deposition, inflammation, DNA damage and apoptosis in H9c2 cells. Mechanistically, Dios activated the SIRT1/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, whereas SIRT1 siRNA abolished Dios-mediated SIRT1/NRF2 activation and cardioprotective effects. Consistent results were observed in vivo, where Dios treatment conferred protection against myocardial injury induced by I/R, as evidenced by the decreased myocardial infarction size, ROS deposition, reduced TUNEL-positive ratio, and improved cardiac function. The protective effects were abolished by EX527. CONCLUSION: Our findings demonstrate that Dios ameliorates myocardial I/R injury by reducing oxidative stress, inflammation, DNA damage, and apoptosis via activating the SIRT1/NRF2 pathway.