AUTHOR=Liu Yihai , Wei Xuan , Wu Mingyue , Xu Jiamin , Xu Biao , Kang Lina 

TITLE=Cardioprotective Roles of β-Hydroxybutyrate Against Doxorubicin Induced Cardiotoxicity

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.603596

DOI=10.3389/fphar.2020.603596

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods and Results:</bold> 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 <italic>in vitro</italic> 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. <italic>In vitro</italic>, BHB treatment decreased cellular injury and apoptosis. Also, BHB alleviated oxidative stress level and increased mitochondrial membrane potential.</p><p><bold>Conclusion:</bold> Our results suggested that BHB could protected from DOX-induced cardiotoxicity by inhibiting cell apoptosis and oxidative stress and maintaining mitochondrial membrane integrity.</p>