To understand the mechanisms of the

To understand the mechanisms of the diosgenin-mediated protection in the DOX-induced deterioration of cardiac function, we assessed the level of cGMP and cAMP in the heart tissue (Figure 1A). The results of our study showed that diosgenin restored the cGMP and cAMP levels (Figure 1A) as well as decreased the PDE5A expression (Figure 1B) in the heart. cGMP and cAMP are intracellular secondary messengers that mediate multiple cellular functions and morphological processes in the heart, including cardiac protection [48] against apoptosis and hypertrophy [49,50].At physiological conditions, cGMP and cAMP are inactivated through hydrolysis degradation via PDE.The PDEs vary in their substrate specificity for cGMP and cAMP, among which PDE5 is specific for cGMP, and PDE3 has a mixed specificity for both cAMP and cGMP [51]. In a murine hypertension model, oral supplement of a PDE5A inhibitor, sildenafil, prevents and reverses cardiac hypertrophy,which is mediated by an activation of cGMP-dependent protein kinase [52]. These results suggest that treatment with PDE5 inhibitors might become a promising therapeutic intervention for preventing the DOX-induced cardiotoxicity, which is consistent with some previous studies [53,54]. cAMP promoted cardiomyocyte survival via an effect mediated through the cAMP pathway and the extracellular signal-regulated kinase activation [55]. Our results demonstrated that diosgenin can rescue the DOX-induced cardiac cell death effect leading to a down-regulation of cardiomyocyte contractility via cAMP-PKA pathway (Figures 1A and 3A).