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Rutaecarpine Inhibits Doxorubicin-Induced Oxidative Stress and Apoptosis by Activating AKT Signaling Pathway

Authors :
Zi-Qi Liao
Yi-Nong Jiang
Zhuo-Lin Su
Hai-Lian Bi
Jia-Tian Li
Cheng-Lin Li
Xiao-Lei Yang
Ying Zhang
Xin Xie
Source :
Frontiers in Cardiovascular Medicine, Vol 8 (2022)
Publication Year :
2022
Publisher :
Frontiers Media S.A., 2022.

Abstract

Patients with cancer who receive doxorubicin (DOX) treatment can experience cardiac dysfunction, which can finally develop into heart failure. Oxidative stress is considered the most important mechanism for DOX-mediated cardiotoxicity. Rutaecarpine (Rut), a quinazolinocarboline alkaloid extracted from Evodia rutaecarpa was shown to have a protective effect on cardiac disease. The purpose of this study is to investigate the role of Rut in DOX-induced cardiotoxicity and explore the underlying mechanism. Intravenous injection of DOX (5 mg/kg, once a week) in mice for 4 weeks was used to establish the cardiotoxic model. Echocardiography and pathological staining analysis were used to detect the changes in structure and function in the heart. Western blot and real-time PCR analysis were used to detect the molecular changes. In this study, we found that DOX time-dependently decreased cardiac function with few systemic side effects. Rut inhibited DOX-induced cardiac fibrosis, reduction in heart size, and decrease in heart function. DOX-induced reduction in superoxide dismutase (SOD) and glutathione (GSH), enhancement of malondialdehyde (MDA) was inhibited by Rut administration. Meanwhile, Rut inhibited DOX-induced apoptosis in the heart. Importantly, we further found that Rut activated AKT or nuclear factor erythroid 2-related factor 2 (Nrf-2) which further upregulated the antioxidant enzymes such as heme oxygenase-1 (HO-1) and GSH cysteine ligase modulatory subunit (GCLM) expression. AKT inhibitor (AKTi) partially inhibited Nrf-2, HO-1, and GCLM expression and abolished the protective role of Rut in DOX-induced cardiotoxicity. In conclusion, this study identified Rut as a potential therapeutic agent for treating DOX-induced cardiotoxicity by activating AKT.

Details

Language :
English
ISSN :
2297055X
Volume :
8
Database :
Directory of Open Access Journals
Journal :
Frontiers in Cardiovascular Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.fbab1804783477e83dd6bacbcb94ac4
Document Type :
article
Full Text :
https://doi.org/10.3389/fcvm.2021.809689