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Updated: Jul 13, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Urolithin A mitigates doxorubicin-induced myocardial injury via suppression of ROS-driven apoptotic signaling
Wei Song1, Mei Chen2, Lin Pang3
1Department of Cardiovascular Medicine, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong, China.
Background:
Doxorubicin (DOX), as a broad-spectrum antitumor drug, achieved great success in the clinic. Nevertheless, severe adverse effects, in particular cardiac toxicity, significantly restrict its clinical utilization. Urolithin A (UA), a metabolite produced by the metabolic activity of intestinal microorganisms on pomegranates, exerts novel protective potential against cardiovascular disease. However, the inhibitory effect of UA against DOX-mediated cardiotoxicity has not been fully explored. Herein, the protective effect and mechanism of UA against DOX-induced cardiotoxicity in vitro and in vivo were investigated.
Methods:
The effects of UA and DOX on cell activity and cell apoptosis were assessed by cell counting Kit-8 (CCK-8), flow cytometry, and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) staining. Reactive oxygen species (ROS) were examined by fluorescent probes. Protein expression was detected by western blotting. A cardiotoxicity rat model was established via injection of DOX to evaluate the in vivo protective mechanism.
Results:
DOX induced obvious ROS-mediated oxidative damage and ultimately led to H9c2 cell apoptosis in vitro and myocardial dysfunction in vivo. However, UA-cotreatment effectively mitigated DOX-induced oxidative damage and apoptosis by regulating the Nrf2 pathway and Bcl-2 family expression, inhibiting ROS, superoxide anions, and MDA generation, enhancing GSH content, and downregulating the ATR-p53 pathway in vitro. Furthermore, UA administration also promoted eNOS activity, inhibited myocardial abnormal proliferation and fibrosis, and improved myocardial function in vivo.
Conclusion:
Our findings validated the rational design that UA has the potential to mitigate DOX-induced myocardial injury in vitro and in vivo by inhibiting ROS-driven apoptosis, which yields significant insights for combating DOX-mediated myocardial injury.
Insights
Urolithin A (UA) protects against Doxorubicin (DOX)-induced heart damage by reducing oxidative stress and apoptosis. This study investigated UA
Area of Science:
- Cardiovascular Pharmacology
- Drug-Induced Toxicity
- Natural Product Metabolites
Background:
- Doxorubicin (DOX) is an effective anticancer drug but causes significant cardiotoxicity.
- Urolithin A (UA), a pomegranate metabolite, shows potential cardiovascular benefits.
- The protective effect of UA against DOX cardiotoxicity requires further investigation.
Purpose of the Study:
- To investigate the protective effect of Urolithin A (UA) against Doxorubicin (DOX)-induced cardiotoxicity.
- To elucidate the underlying mechanisms of UA's cardioprotective action both in vitro and in vivo.
Main Methods:
- Cell viability and apoptosis assays (CCK-8, flow cytometry, TUNEL) were used to assess in vitro effects.
- Reactive oxygen species (ROS) and protein expression (Western blotting) were analyzed.
- A rat model of DOX-induced cardiotoxicity was established to evaluate in vivo mechanisms.
Main Results:
- DOX induced oxidative damage and apoptosis in H9c2 cells and myocardial dysfunction in rats.
- UA mitigated DOX-induced damage by inhibiting ROS, regulating Nrf2 and Bcl-2 family expression, and downregulating the ATR-p53 pathway.
- UA improved cardiac function, promoted eNOS activity, and reduced myocardial fibrosis in vivo.
Conclusions:
- Urolithin A effectively mitigates Doxorubicin-induced myocardial injury.
- UA's protective mechanism involves inhibiting ROS-driven apoptosis.
- These findings offer insights for managing Doxorubicin-mediated cardiotoxicity.
