Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway
- 23 March 2023
- journal article
- research article
- Published by Royal Society of Chemistry (RSC) in Food & Function
- Vol. 14 (8), 3849-3862
- https://doi.org/10.1039/d2fo03904d
Abstract
Doxorubicin (DOX) is used extensively in anticancer therapy, but its clinical application is limited due to its cardiotoxicity. Carnosic acid (CA) is a bioactive compound found in rosemary. It has been shown to reduce inflammation and reactive oxygen species. The purpose of this study was to investigate the potential cardioprotective effects of CA in response to DOX-induced cardiotoxicity. Here, C57BL/6 mice were administered an intraperitoneal injection of DOX (5 mg kg−1, ip) once a week for three consecutive weeks and treated with CA (40 mg kg−1, ig) for a three-week experimental period. For in vitro study, neonatal rat ventricular cardiomyocytes were used to validate the protective effects of CA (20 μM) in response to DOX-induced cardiotoxicity. CA markedly suppressed oxidative stress, apoptosis, and pyroptosis responses in the mouse hearts, eventually improving cardiac function. CA showed its antioxidant effect by activating nuclear factor erythroid 2-related factor (Nrf2) and its downstream heme oxygenase-1 (HO-1); CA also reduced oxidative stress by lowering the MDA and lipid ROS levels and raising the SOD and GSH-px levels. Additionally, CA treatment significantly increased Bcl-2 and inhibited Bax and Caspase-3 cleavage in DOX-induced cardiotoxicity. Moreover, CA suppressed the NOD-like receptor protein 3 (NLRP3) pathway to mitigate pyroptosis, as evidenced by lowered caspase1, interleukin-18, and interleukin-1β. Consistently, the transfection of Nrf2-siRNA eliminated the protective effects of CA on cardiomyocytes. Altogether, our findings demonstrated that CA inhibited NLRP3 inflammasomes via activating the Nrf2-related cytoprotective system and protected the heart from oxidative damage, apoptosis, and pyroptosis, implying that the use of CA could be a potential therapeutic strategy in the prevention of DOX-associated myocardiopathy.Funding Information
- National Natural Science Foundation of China (81870301, 82270243)
This publication has 38 references indexed in Scilit:
- Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree?Redox Biology, 2019
- Ginsenoside Rg1 protects mice against streptozotocin-induced type 1 diabetic by modulating the NLRP3 and Keap1/Nrf2/HO-1 pathwaysEuropean Journal of Pharmacology, 2019
- The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and RegulationInternational Journal of Molecular Sciences, 2019
- FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKTCell Death & Differentiation, 2019
- Involvement of Nrf2 in myocardial ischemia and reperfusion injuryInternational Journal of Biological Macromolecules, 2018
- Targeting the NLRP3 inflammasome in inflammatory diseasesNature Reviews Drug Discovery, 2018
- Nrf2 at the heart of oxidative stress and cardiac protectionPhysiological Genomics, 2018
- MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2Redox Biology, 2017
- Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicityOncotarget, 2017
- Tanshinone IIA sodium sulfonate protects against cardiotoxicity induced by doxorubicin in vitro and in vivoFood and Chemical Toxicology, 2009