Dioscin ameliorates doxorubicin‐induced heart failure via inhibiting autophagy and apoptosis by controlling the PDK1‐mediated Akt/mTOR signaling pathway

Abstract

Heart failure (HF) is a disease with high mortality and morbidity rate. Autophagy is critically implicated in HF progression. The current research was designed to investigate the function of Dioscin on oxidative stress, autophagy, and apoptosis in HF. In this study, doxorubicin (Dox) was employed to induce HF model and HL‐1 cell damage model. Echocardiography implied that Dioscin could dramatically relieve heart function in vivo. Western blotting determined that Dioscin treatment reversed the promotive effect of autophagy caused by Dox through modulating levels of key autophagy‐associated molecules, including Atg5 and Beclin1. Dioscin also impaired apoptosis by regulating apoptosis‐related protein, including Bcl‐2 and cleaved caspase‐3 following Dox treatment in vivo and in vitro. Furthermore, the impacts of Dioscin were mediated by upregulation of PDK1‐mediated Akt/mTOR signaling. The mTOR inhibitor (rapamycin) could counteract the therapeutic impact of Dioscin in vitro. Taken together, Dioscin could relieve cardiac function through blocking apoptosis and autophagy by activating the PDK1‐elicited Akt/mTOR pathway.

Autophagy and Senescence: The Molecular Mechanisms and Implications in Liver Diseases

“…PIP3 binds to Akt/protein kinase B and phosphoinositide-dependent kinase-1 (PDK1). PDK1 then phosphorylates AKT, which in turn phosphorylates mTOR to inhibit autophagy [24]. Mammalian target of rapamycin complex 1 (mTORC1) signaling negatively regulates the activity of the unc-51-like autophagy-activating kinase (ULK)1 complex [25] (Figure 2).…”

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis

“…This protective mechanism is associated with the modulation of miR-140-5p-mediated myocardial oxidative stress under the initiation of the Nrf2/sirtuin 2 pathway [20]. Additionally, Yuan et al reported that dioscin modulates the phosphoinositide-dependent protein kinase-1 (PDK1)-regulated Akt/mammalian target of rapamycin (mTOR) pathway to improve DOX-induced heart failure (intraperitoneal injection of 2.5 mg/kg DOX six times in 2 weeks) [21]. These results provide evidence that the therapeutic effect of dioscin on acute DIC may be related to Nrf2-associated oxidative stress.…”