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FoxO3 Activation Alleviates Doxorubicin-Induced Cardiomyopathy by Enhancing Autophagic Flux and Suppressing mTOR/ROS
Zao-Shang Chang1,2, Le Wang1, Ju-Xiang Zhou3
1Department of Physiology, Pu ai Medical School, Shaoyang University, Shaoyang, Hunan, China.
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.
Insights
Doxorubicin-induced cardiomyopathy is mitigated by enhancing the transcription factor FoxO3. Overexpressing FoxO3 boosts protective autophagy, reducing oxidative stress and heart damage.
Area of Science:
- Biochemistry
- Cardiology
- Molecular Biology
Background:
- Doxorubicin (DOX) is a potent chemotherapy agent with dose-limiting cardiotoxicity.
- The role of the transcription factor FoxO3 in DOX-induced cardiomyopathy is not fully understood.
- DOX-induced cardiotoxicity manifests as cardiac atrophy, dysfunction, fibrosis, and mitochondrial damage.
Purpose of the Study:
- To investigate the protective role of FoxO3 in DOX-induced cardiotoxicity.
- To elucidate the molecular mechanisms by which FoxO3 influences autophagy and oxidative stress in cardiomyocytes.
- To evaluate FoxO3 as a potential therapeutic target for mitigating DOX-induced heart damage.
Main Methods:
- Assessed DOX effects on H9c2 cardiomyocyte viability, oxidative stress markers (ROS, MDA, GSH), and enzyme activity (LDH, SOD2, CAT).
- Examined the impact of DOX on FoxO3 activation and autophagy markers (LC3 II/I ratio).
- Investigated the effects of FoxO3 overexpression and autophagy modulators (BafA1, Rapa) on cellular and molecular pathways in vitro and in vivo.
Main Results:
- DOX exposure reduced cardiomyocyte viability, increased oxidative stress and LDH, and suppressed SOD2/CAT expression.
- DOX inhibited FoxO3 activation and altered autophagy markers.
- Overexpression of FoxO3 enhanced autophagy (LC3B, Beclin 1, autophagic flux), reduced p62, and suppressed mTOR activation.
- FoxO3 overexpression attenuated DOX-induced ROS production and mTOR activation in vitro and in vivo.
Conclusions:
- FoxO3 plays a crucial protective role against DOX-induced cardiotoxicity.
- FoxO3 enhances protective autophagy, suppresses oxidative stress, and inhibits mTOR signaling.
- Targeting FoxO3 to promote autophagy presents a promising therapeutic strategy for preventing or treating DOX-induced cardiomyopathy.
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