Total flavonoids of Selaginella tamariscina (P.Beauv.) Spring ameliorates doxorubicin-induced cardiotoxicity by modulating mitochondrial dysfunction and endoplasmic reticulum stress via activating MFN2/PERK

• Published in: Phytomedicine (Stuttgart) 2022-06, Vol.100, p.154065-154065, Article 154065
• Main Authors: Gao, Liyuan, Yuan, Peipei, Wei, Yaxin, Fu, Yang, Hou, Ying, Li, Panying, Chen, Yi, Ruan, Yuan, Zhou, Ning, Zheng, Xiaoke, Feng, Weisheng
• Format: Article
• Language: English
• Subjects: apoptosis; body weight; Cardiotoxicity; Doxorubicin; drug therapy; echocardiography; endoplasmic reticulum; Endoplasmic reticulum stress; energy metabolism; flavonoids; flow cytometry; heart; heart failure; histology; membrane potential; MFN2/PERK; mitochondria; mitochondrial membrane; oxidative stress; reactive oxygen species; Selaginella tamariscina; Total flavonoids of Selaginella tamariscina (P.Beauv.) Spring
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2022.154065

Doxorubicin (DOX) is a highly effective chemotherapeutic that is effective for various tumours. However, the clinical application of DOX has been limited by adverse reactions such as cardiotoxicity and heart failure. Since DOX-induced cardiotoxicity is irreversible, drugs to prevent DOX-induced cardiotoxicity are needed. This study aimed to investigate the effect of total flavonoids of Selaginella tamariscina (P.Beauv.) Spring (TFST) on doxorubicin-induced cardiotoxicity. The present study established DOX-induced cardiotoxicity models in C57BL/6 mice treated with DOX (cumulative dose: 20 mg/kg body weight) and H9c2 cells incubated with DOX (1 μM/l) to explore the intervention effect and potential mechanism of TFST. Echocardiography was performed to evaluate left ventricular functions. Heart tissue samples were collected for histological evaluation. Myocardial injury markers and oxidative stress markers were examined. Mitochondrial energy metabolism pathway associated proteins PPARα/PGC-1α/Sirt3 were detected. We also explored the effects of TFST on endoplasmic reticulum (ER) stress and apoptosis. To further investigate the protective mechanism of TFST, we used the specific small interfering RNA MFN2 (siMFN2) to explore the effect of MFN2 on TFST against DOX-induced cardiotoxicity in vitro. Flow cytometry detected reactive oxygen species, mitochondrial membrane potential and apoptosis. Cell mitochondrial stress was measured by Seahorse XF analyser. Both in vivo and in vitro studies verified that TFST observably alleviated DOX-induced mitochondrial dysfunction and ER stress. However, these effects were reversed after transfected siMFN2. Our results indicated that TFST ameliorates DOX-induced cardiotoxicity by alleviating mitochondrial dysfunction and ER stress by activating MFN2/PERK. MFN2/PERK pathway activation may be a novel mechanism to protect against DOX-induced cardiotoxicity. Selaginella tamariscina (P.Beauv.) Spring (TFST) is used in folk medicine to treat many diseases, including hyperglycemia, diabetes, cardiovascular disorders and cancers. It contains a large amount of flavonoids, which have a variety of biological activities. This study aimed to investigate the effect of TFST on doxorubicin (DOX)-induced cardiotoxicity and the underlying mechanisms involved. The results indicated that TFST had a protective effect on DOX-induced cardiotoxicity, which could ameliorate DOX-induced cardiotoxicity by alleviating mitochondrial dysfunction and ER stres