Ferruginol Restores SIRT1-PGC-1α-Mediated Mitochondrial Biogenesis and Fatty Acid Oxidation for the Treatment of DOX-Induced Cardiotoxicity

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.

Role of Terpenophenolics in Modulating Inflammation and Apoptosis in Cardiovascular Diseases: A Review

“…Ferruginol effectively attenuated myocardial injury caused by overdosed isoprenaline hydrochloride by reducing cardiac injury markers: cardiac troponin-T (cTnT), cardiac troponin-I (cTnI), creatine kinase (CK), and creatine kinase-MB (CKMB) in myocardial infarction model [ 44 ]. This finding supports the latest study by Li et al [ 45 ] that demonstrated that ferruginol reduced cardiac injury markers in the doxorubicin (DOX)-induced cardiotoxicity model. Furthermore, ferruginol exerted its antioxidant properties in the reduction of lipid peroxidation markers and malondialdehyde (MDA) and upregulated the antioxidant enzymes SOD, GPx, catalase (CAT), and glutathione (GSH).…”

Synergistic Effects of Ginsenoside Rb3 and Ferruginol in Ischemia-Induced Myocardial Infarction

“…G-Rb3, the main component of Sanqi, was shown to e a protective effect on the myocardium by improving energy metabolism, suppressing idative stress and improving microcirculation disorders [18,20,37]. FGL is a natural p phenol and terpenoid compound that was shown to play a cardioprotective role in mod of doxorubicin-induced myocardial injury [31]. Owing to the complexity of serious eases, such as myocardial infarction, recent developments have gradually shifted fro focus on monotherapy to combined or multiple therapies because the synergy of th peutic agents or techniques results in ostentatious super additive (namely "1 + 1 > MI results from the irreversible death of cardiomyocytes which caused by prolonged hypoxia or inadequate blood supply [33].…”

“…For example, our research found that G-Rb3 exerts a cardio-protective effect by inhibiting apoptosis and up-regulating energy metabolism [18]. FGL restores mitochondrial biogenesis and FAO for the treatment of doxorubicin-induced cardiotoxicity [31]. However, whether FGL can improve the effectiveness of G-Rb3 in the treatment of myocardial infarction remains unclear.…”

Mitochondria and Doxorubicin-Induced Cardiomyopathy: A Complex Interplay

“…Increased mitochondrial biogenesis was observed in DOX-treated mice that received ferruginol, a pharmacological activator of PPARγ coactivator 1 alpha (PGC-1α), the master regulator of mitochondrial biogenesis. This was associated with increased fatty acid oxidation, mitochondrial function, and myocardial integrity [65].…”