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Superoxide Mediates Radiation-Induced Cardiac Injury and Activates the Canonical Transforming Growth Factor-Beta
Kranti A Mapuskar1, Casey F Pulliam1, Ann Tomanek-Chalkley1
1University of Iowa Healthcare Free Radical and Radiation Biology Program, Department of Radiation Oncology Iowa City 52242 IA USA.
Journal of the American Heart Association
|December 23, 2025
Summary
This study shows that a superoxide dismutase mimetic, RUC, protects the heart from radiation damage by improving mitochondrial function and reducing fibrosis. RUC treatment improved survival and cardiac function after radiation injury.
Area of Science:
- Cardiovascular Science
- Radiation Oncology
- Mitochondrial Biology
Background:
- Therapeutic ionizing radiation for thoracic cancers can harm cardiovascular tissues.
- Mitochondrial dysfunction and oxidative stress are key factors in radiation-induced heart damage.
- Targeting mitochondria is crucial for mitigating radiation cardiotoxicity while preserving anti-cancer efficacy.
Purpose of the Study:
- To investigate the cardiopulmonary effects of cardiac targeted radiation injury (CTI) in a mouse model.
- To evaluate the protective potential of the superoxide dismutase (SOD) mimetic, ulinastatin (RUC), against CTI-induced cardiovascular toxicities.
- To explore the impact of RUC on mitochondrial function and associated signaling pathways post-radiation.
Main Methods:
- A cardiac targeted radiation injury (CTI) model was established in C57BL/6J female mice using a single 16 Gy radiation dose.
- Mice received ulinastatin (RUC) starting 1 hour before CTI, with daily treatment for 1 week and weekly thereafter for 9 months.
- Cardiopulmonary implications were assessed, including cardiac function via echocardiography, mitochondrial protein analysis, and assessment of the TGF-β/Smad pathway.
Main Results:
- All irradiated mice exhibited CTI-induced cardiovascular toxicities.
- RUC treatment significantly improved overall survival and alleviated cardiac dysfunction.
- RUC attenuated persistent changes in mitochondrial oxidative phosphorylation proteins and TCA cycle enzymes, reduced cardiac fibrosis, and inhibited the TGF-β/Smad pathway.
Conclusions:
- Selective SOD mimetics like RUC demonstrate a novel protective role against CTI-induced cardiovascular toxicities.
- Superoxide is implicated in modulating mitochondrial function, TGF-β/Smad pathway activation, and radiation-induced heart side effects.
- RUC treatment shows potential for antagonizing the TGF-β pathway, warranting further mechanistic investigation.
Keywords:
cardiac fibrosiscardiac‐targeted radiation injuryionizing radiationrucosopasemsuperoxide dismutase mimetictransforming growth factor‐betaMore Related Videos
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