Abstract
Background: Doxorubicin (DOX), a broad-spectrum chemotherapy drug, has life-threatening cardiotoxicity. Therefore, searching cardioprotective drugs for DOX-induced cardiotoxicity (DIC) is urgently needed. Objectives: This study aimed to explore cardioprotective effect and specific mechanism by which Ferruginol (FGL) attenuated DIC in vivo and in vitro. Methods: We evaluated the cardioprotection of FGL and performed high-throughput RNA-Seq on a DIC mouse. Whereafter, multiple methods, including western blot, RT-qPCR, a transmission electron microscope, CO-IP, immunofluorescence, and other staining methods, and antagonist of SIRT1 and PGC-1α were utilized to confirm the cardioprotection and molecular mechanism of FGL. Results: FGL-exerted cardioprotection manifested as enhanced cardiac function and reduced structural damage and apoptosis. The transcriptome and other results revealed that FGL facilitated PGC-1α-mediated mitochondrial biogenesis and fatty acid oxidation (MB and FAO) by increasing the expression of PGC-1α and concurrently promoting the expression of SIRT1-enhancing deacetylase SIRT1 deacetylating and activating PGC-1α. Conclusions: These results documented that FGL exerted cardioprotective effects restoring MB&FAO via the SIRT1–PGC-1α axis.
Highlights
The anthracycline antibiotic doxorubicin (DOX) is widely used as an effective chemotherapeutic drug for a wide range of cancers (Carter, 1975; Carvalho et al, 2009)
We found that DOX caused a large amount of ROS production, while FGL significantly reduced ROS production. These results suggested that FGL alleviated apoptosis and ROS production by associating with SIRT1 and PGC-1α
Combined with reported research that SIRT1 deacetylated PGC-1α and activated its transcriptional activity, we proposed that FGL
Summary
The anthracycline antibiotic doxorubicin (DOX) is widely used as an effective chemotherapeutic drug for a wide range of cancers (Carter, 1975; Carvalho et al, 2009). The dose-dependent cardiotoxicity of DOX severely limits its clinical application. GRAPHICAL ABSTRACT | Graphical abstract of the pathogenic mechanism of DOX and the cardioprotective mechanism of FGL. Dexrazoxane is the only cardioprotectant currently approved by the United States Food and Drug Administration for combining with DOX in cancer therapy (Schuchter et al, 2002; Kane et al, 2008). A new cardioprotectant for DOX-induced cardiotoxicity (DIC) is urgently needed. Doxorubicin (DOX), a broad-spectrum chemotherapy drug, has lifethreatening cardiotoxicity. Searching cardioprotective drugs for DOXinduced cardiotoxicity (DIC) is urgently needed
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