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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.