Abstract
Background: β-Hydroxybutyrate (BHB) is produced by fatty acid oxidation in the liver under the fasting state and confirmed to play a cardioprotective role in ischemia and hypertensive settings. Doxorubicin (DOX) is an effective chemotherapeutic drug, but limited by serious irreversible cardiotoxicity. However, whether BHB can protect from DOX-induced cardiotoxicity remains unknown. Methods and Results: C57BL/6 mice were intraperitoneally injected with DOX to induce cardiac toxicity and intragastrically administered into BHB for treatment. They were randomly divided into three groups, namely a sham group (Sham), a doxorubicin group (DOX), and a doxorubicin+β-Hydroxybutyrate group (DOX + BHB). Echocardiography and pathological staining were performed to evaluate cardiac function and fibrosis. H9c2 cardiomyocyte was treated with DOX or BHB for in vitro experiments. Cell apoptosis and ROS were determined by flow cytometry. BHB significantly restored DOX-induced cardiac function decline and partially prevented cardiac reverse remodeling, characterized by increased cell size and decreased fibrosis. In vitro, BHB treatment decreased cellular injury and apoptosis. Also, BHB alleviated oxidative stress level and increased mitochondrial membrane potential. Conclusion: Our results suggested that BHB could protected from DOX-induced cardiotoxicity by inhibiting cell apoptosis and oxidative stress and maintaining mitochondrial membrane integrity.
Highlights
Doxorubicin (DOX) is widely recognized as antineoplastic for the treatment of several malignant tumors including solid tumors, leukemia and lymphoma (Minotti et al, 2004)
We evaluated the cardioprotective effect of BHB on doxorubicin group (DOX)-induced cardiotoxicity in vitro and in vivo
Β-Hydroxybutyrate Preventing from Cardiotoxicity treatment led to a significant decrease in ejection fraction (EF)
Summary
Doxorubicin (DOX) is widely recognized as antineoplastic for the treatment of several malignant tumors including solid tumors, leukemia and lymphoma (Minotti et al, 2004). Its clinical use is limited by severe cardiotoxic side effects, including arrhythmia, dilated cardiomyopathy and subsequent heart failure (Octavia et al, 2012). Researchers over the past two decades had demonstrated that ROS production (Liu et al, 2020), cell apoptosis (Yu et al, 2020) and autophagy (Sun et al, 2014; Ma et al, 2017), DNA damage (Mizuta et al, 2020), mitophagy (Liang et al, 2020; Xu et al, 2020) and various signaling pathways (Chen et al, 2020) were the potential mechanisms, providing further insight into treatment strategies to prevent the DOX-induced cardiotoxic effects. It was no effective to utilize various kind of antioxidant agents to suppress oxidative stress in the clinical β-Hydroxybutyrate Preventing from Cardiotoxicity trials. No treatment is unanimously recommended for attenuating DOX-induced cardiotoxicity, indicating the need for further investigations (Varricchi et al, 2018)
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