FoxO3 Activation Alleviates Doxorubicin-Induced Cardiomyopathy by Enhancing Autophagic Flux and Suppressing mTOR/ROS Signalling

Abstract

Doxorubicin (DOX) is an effective chemotherapy drug, but its use is limited by cardiotoxicity, known as DOX-induced cardiomyopathy. The transcription factor FoxO3, which regulates autophagy and oxidative stress, has unclear mechanisms in this condition. We found that DOX-induced cardiomyopathy involved cardiac atrophy, cardiac dysfunction, fibrosis and mitochondrial damage. DOX reduced H9c2 cardiomyocyte viability and glutathione levels (GSH), increased reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) and inhibited superoxide dismutase 2 (SOD2) and catalase (CAT) expression. DOX also suppressed FoxO3 activation and increased the autophagy protein LC3 II/I ratio. Overexpressing FoxO3 enhanced LC3B, Beclin 1 and autophagic flux, while reducing p62 and suppressing mTOR activation in heart. Brefeldin A1 (BafA1), an autophagy inhibitor and rapamycin (Rapa), an autophagy activator, were administered to H9c2 cardiomyocytes to elucidate the regulatory mechanism of FoxO3. Mechanically, our data revealed that FoxO3 overexpression enhanced autophagy and suppressed ROS production and mTOR activation in both in vitro and in vivo models of DOX exposure. Collectively, targeting FoxO3 to enhance protective autophagy may offer a therapeutic strategy against DOX-induced cardiomyopathy.

Keywords: FoxO3; autophagy; cardiomyopathy; doxorubicin; reactive oxygen species.