Hesperetin modulates the Sirt1/Nrf2 signaling pathway in counteracting myocardial ischemia through suppression of oxidative stress, inflammation, and apoptosis.

Hesperetin (HSP) is a natural flavonoid that offers useful curative effects for cardiovascular diseases, but its effect on myocardial ischemia and its precise mechanism remains unclear. The aim of this study is to explore the potential cardioprotective mechanism of HSP on myocardial ischemia caused by isoproterenol (ISO). Adult male Kunming mice were randomly divided into five groups: control, ISO, low-dose HSP (L-HSP, 25 mg/kg/d), high-dose HSP (H-HSP, 50 mg/kg/d), and verapamil (VER) group. Treatment groups of mice received HSP or VER for seven days, and the groups other than the control group were injected with ISO (100 mg/kg/d) subcutaneously for two consecutive days to establish a model of myocardial ischemia. Electrocardiogram and heart-histology changes were used to assess changes in myocardial architecture. The activities and the content of oxidative stress markers and inflammatory cytokines were determined and assayed using kits respectively. The expressions of proteins associated with apoptosis and the Sirt1/Nrf2 pathway were evaluated by Western blotting. The results demonstrate that VER, L-HSP and H-HSP significantly reduced the J-point displacement, heart rate, cardiac pathomorphological changes, and the levels of creatine kinase, lactated dehydrogenase, malonaldehyde, interleukin-6, and tumor necrosis factor-α in serum while promoting the activation of superoxide dismutase, catalase, glutathione in serum in the ISO-treated animals. Furthermore, L-HSP and H-HSP also reversed the ISO-induced apoptosis and the changes in the Sirt1/Nrf2 signaling pathway, as evident from the levels of proteins Bax, Bcl-2, caspase-3, Sirt1, Nrf2, NQO-1, and HO-1. In conclusion, HSP plays a protective role in ISO-induced myocardial ischemia by modulating oxidative stress, inflammation, and apoptosis via Sirt1/Nrf2 pathway activation.