7,8,3'-Trihydroxyflavone prevents doxorubicin-induced cardiotoxicity and mitochondrial dysfunction via activating Akt signaling pathway in H9c2 cells

Abstract

Clinical application of the widely used chemotherapeutic agent, doxorubicin (DOX), is limited by its cardiotoxicity. Mitochondrial dysfunction has been revealed as a crucial factor in DOX-induced cardiotoxicity. 7,8,3'-Trihydroxyflavone (THF) is a mimetic brain-derived neurotrophic factor with neuroprotective effects. However, the potential effects of THF on DOX-induced cardiomyocyte damage and mitochondrial disorders remain unclear. H9c2 cardiomyoblasts were exposed to DOX and/or THF at different concentrations. Cardiomyocyte injury was evaluated using lactate dehydrogenase (LDH) assay and Live/Dead cytotoxicity kit. Meanwhile, mitochondrial membrane potential (MMP), morphology, mitochondrial reactive oxygen species (mito-ROS) production, and the oxygen consumption rate of cardiomyocytes were measured. The protein levels of key mitochondria-related factors such as adenosine monophosphate-activated protein kinase (AMPK), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and optic atrophy protein 1 (OPA1) were examined. We found that THF reduced LDH content and death ratio of DOX-treated cardiomyocytes in a concentration-dependent manner, while increasing MMP without significantly affecting the routine and maximum capacity of mitochondrial respiration. Mechanistically, THF increased the activity of Akt and protein levels of Mfn2 and heme oxygenase 1 (HO-1). Moreover, inhibition of Akt reversed the protective role of THF, increased mito-ROS levels, and repressed Mfn2 and HO-1 expression. Therefore, we conclude, THF relieves DOX-induced cardiotoxicity and improves mitochondrial function by activating Akt-mediated Mfn2 and HO-1 pathways. This finding provides promising therapeutic insights for DOX-induced cardiac dysfunction.

Keywords: 7,8,3′-Trihydroxyflavone; Akt; Cardiotoxicity; Doxorubicin; Mitochondria.