Effects of ivabradine on myocardial autophagia and apoptosis in isoprenaline-induced heart failure in mice

Objective(s): To investigate the effects and mechanisms of ivabradine (IVA) on isoprenaline-induced cardiac injury.Materials and Methods: Forty male C۵۷BL/۶ mice were randomly divided into control group, model group, high-dose IVA group, and low-dose IVA group. The control group was given saline, other groups were given subcutaneous injections of isoproterenol (ISO) ۵ mg/kg/d to make the myocardial remodeling model. A corresponding dose of IVA (high dose ۵۰ mg/kg/d, low dose ۱۰ mg/kg/d) was given by gavage (۳۰ days). A transthoracic echocardiogram was obtained to detect the structure and function of the heart. An electron microscope was used to explore the cardiomyocytes’ apoptosis and autophagy. HE staining and Masson’s trichrome staining were performed to explore myocardial hypertrophy and fibrosis. Western blot was used to detect Bax, Bcl-۲, cleaved caspase-۳, Becline-۱, LC۳, phosphorylated p۳۸ mitogen-activated protein kinase (p-p۳۸MAPK), phosphorylated extracellular regulated protein kinases۱/۲ (p-ERK۱/۲), phosphorylated c-Jun N-terminal kinase (p-JNK), and α-smooth muscle actin (α-SMA) in the myocardium.Results: Heart rate in the IVA groups was reduced, and the trend of heart rate reduction was more obvious in the high-dose group. Echocardiography showed that IVA improved the cardiac structure and function compared to the model group. IVA attenuated cardiac fibrosis, decreased cardiomyocyte apoptosis, and increased autophagy. The phosphorylated MAPK in the ISO-induced groups was increased. IVA treatment decreased the p-p۳۸MAPK level. There were no differences in p-ERK and p-JNK levels.Conclusion: The beneficial effects of IVA on myocardial injury are related to blocking the p۳۸MAPK signal pathway, decreasing cardiomyocyte apoptosis, and increasing cardiomyocyte autophagy.

کلیدواژه ها:

Apoptosis ، Autophagy ، Cardiac remodeling ، Fibrosis ، heart failure