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Superoxide Mediates Radiation-Induced Cardiac Injury and Activates the Canonical Transforming Growth Factor-Beta Signaling Pathway
Journal article   Open access   Peer reviewed

Superoxide Mediates Radiation-Induced Cardiac Injury and Activates the Canonical Transforming Growth Factor-Beta Signaling Pathway

Kranti A Mapuskar, Casey F Pulliam, Ann Tomanek-Chalkley, Jason Dierdorff, Kyle Current, Robert A Beardsley, Barry London and Bryan G Allen
Journal of the American Heart Association, Vol.15(1), e042101
01/2026
DOI: 10.1161/JAHA.125.042101
PMCID: PMC12909022
PMID: 41431993
Appears in  UI Libraries Support Open Access
url
https://doi.org/10.1161/JAHA.125.042101View
Published (Version of record) Open Access

Abstract

Therapeutic ionizing radiation is a standard treatment modality for thoracic cancers that may affect surrounding normal tissues, including the cardiovascular system. The increasing recognition of mitochondrial health in cellular responses to oxidative stress, particularly in ionizing radiation-induced cardiac implications, highlights mitochondria as a critical target for therapeutic interventions. Optimizing mitochondrial function to attenuate ionizing radiation-induced cardiac pathology necessitates balancing killing cancer cells with sparing nonmalignant tissues. Using a cardiac targeted radiation injury (CTI) model of injury, C57BL/6J female mice were exposed to a single 16 Gy dose and treated with an SOD (superoxide dismutase) mimetic, ucosopasem manganese (RUC) starting 1 hour before CTI, continued daily for 1 week post CTI, and once per week thereafter until euthanasia to investigate cardiopulmonary implications over 9 months. CTI cardiovascular toxicities were observed in all irradiated mice. RUC significantly increased overall survival and alleviated CTI-induced changes in cardiac function as assessed by cardiac echocardiography. Persistent changes in mitochondrial oxidative phosphorylation proteins and tricarboxylic acid cycle enzymes were notably attenuated following RUC treatment. Interestingly, RUC reduced both CTI-induced cardiac fibrosis and the activation of the TGF-β/Smad (transforming growth factor-beta/suppressor of mothers against decapentaplegic transcription factor family) pathway. This study presents a novel role for selective superoxide dismutase mimetics, such as RUC, in protecting against CTI-induced cardiovascular toxicities. As RUC dismutates superoxide, the results suggest superoxide plays a key part in the modulation of mitochondrial oxidative phosphorylation, activation of the canonical TGF-β/Smad pathway, and ionizing radiation cardiovascular side effects. These findings suggest an association between RUC treatment and TGF-β pathway antagonism that requires additional mechanistic validation.
 superoxide dismutase mimetic transforming growth factor‐beta cardiac fibrosis cardiac‐targeted radiation injury ionizing radiation rucosopasem UIOWA OA Agreement

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