Icariside Ⅱ alleviates heart failure based on Wnt/β-catenin-mitochondrial apoptotic pathway

Heart failure (HF) represents a major global health challenge. This condition is closely linked to the dysregulation of a key signaling mechanism known as the Wnt/β-catenin pathway. Using an isoproterenol (ISO)-induced mice model of HF and H9c2 cells injury, we examined the effects of Icariside II (ICS II) on ventricular remodeling and apoptosis, focusing on the Wnt/β-catenin and mitochondrial apoptotic pathways. ICS II significantly improved cardiac function, reduced left ventricular hypertrophy, and decreased expression of the HF markers atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). In HF mice treated with ICS II, Western blot analysis revealed reduced levels of both Wnt/β-catenin pathway proteins and apoptotic markers in cardiac tissue. Consistent with these in vivo findings, ICS II also protected H9c2 cells from ISO-induced injury in vitro. This protection was accompanied by a decrease in cell area and apoptosis, as well as a similar suppression of Wnt/β-catenin pathway proteins. GSK-3β inhibitor SB216763 reversed ICS II's protective effects, increasing H9c2 cells apoptosis and restoring Wnt/β-catenin pathway activity (except Wnt3A). These findings demonstrate that ICS II alleviates HF by modulating the Wnt/β-catenin-mitochondrial apoptotic pathway. Given that this compound improves cardiac function while simultaneously addressing pathological remodeling and apoptosis, it holds promise as a new therapeutic approach for HF.