Engeletin mediates antiarrhythmic effects in mice with isoproterenol-induced cardiac remodeling

Objective: Engeletin is a potent natural compound with antioxidant and anti-inflammatory properties. However, its role in cardiac remodeling remains unclear. Herein, the aim of the present study was to explore the effects of engeletin on cardiac structural and electrical remodeling and its underlying mechanism. Methods: and results: A cardiac remodeling mice model using isoproterenol (ISO)-induced myocardial fibrosis was constructed and divided into the following four groups: control group; engeletin group; ISO group; engeletin + ISO group. Our results demonstrated that engeletin alleviated ISO-induced myocardial fibrosis and dysfunction. Moreover, engeletin significantly prolonged the QT and corrected QT (QTc) intervals, effective refractory period (ERP), and action potential duration (APD), and enhanced connexin protein 43 (Cx43) and ion channel expressions, thereby decreasing ventricular fibrillation (VF) susceptibility. Additionally, dihydroethidium staining illustrated that engeletin decreased reactive oxygen species (ROS) production. Of note, engeletin also increased the levels of superoxide dismutase and glutathione and decreased the activity of malondialdehyde and L-Glutathione oxidized. Moreover, engeletin significantly increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Furthermore, in vitro administration of an Nrf2 inhibitor abolished the anti-oxidant properties of engeletin. Conclusion: Engeletin ameliorated cardiac structural and electrical remodeling, ion channel remodeling, and oxidative stress induced by ISO in mice, thereby reducing VF susceptibility. These effects may be attributed to the anti-oxidant properties of engeletin associated with the Nrf2/HO-1 pathway.