Sex-dependent Impairment of Nitric Oxide Signaling and Mitochondrial Metabolism in Radiation-Induced Cardio-Pulmonary Dysfunction - Whether accidental or intentional, ionizing radiation (IR) exposure poses significant risks to thoracic organs, particularly the heart and lungs. It can lead to inflammation, fibrosis, and cellular senescence, resulting in a range of clinical complications. These include pericarditis, coronary artery disease, valvular issues, heart failure, arrhythmias, radiation pneumonitis, pulmonary fibrosis, and even mortality. Notably, there are sex- based differences in how individuals respond to IR, with women often displaying greater susceptibility to long- term IR toxicities. The exact mechanisms behind these sex-based disparities are still unclear, but they may involve factors such as hormones, genetics, and metabolism. Nitric oxide synthase 1 plays a crucial role in catalyzing nitric oxide biosynthesis. Preliminary research in mice exposed to 20 Gy cardiac-targeted IR showed that they developed heart and lung abnormalities, including diastolic dysfunction, conduction issues, cardiac fibrosis, and pulmonary congestion. However, male mice exhibited additional problems including left ventricular dilation, systolic dysfunction, and alterations in mitochondrial electron transport chain complex II activity. Interestingly, both male and female mice with decreased nitric oxide synthase 1 expression exposed to 20 Gy experienced reduced left ventricular size and function, faster atrioventricular conduction, and no evidence of diastolic dysfunction. Treatment with a superoxide dismutase mimetic, Rucosopasem, mitigated some of the IR-induced cardiac changes in female mice. This data implies that sex-related differences in nitro-oxidative pathways and disruptions in the mitochondrial electron transport chain metabolism could influence sensitivity to cardio-thoracic IR. We hypothesize that IR-induced, sex-dependent alterations in redox signaling pathways stemming from differences in mitochondrial electron transport chain activities between males and females lead to changes in reactive oxygen species and reactive nitrogen species, which in turn mediate IR-induced cardiac and pulmonary dysfunction. Aim 1 will use an upper body model of IR exposure to investigate the sex-based effects of IR on mitochondrial oxidative metabolism in wildtype and heterozygous nitric oxide synthase 1 disrupted mice, its role in generating reactive oxygen and reactive nitrogen species, and its impact on cardio- pulmonary function. Aim 2 will assess the effectiveness of Rucosopasem, a superoxide dismutase mimetic, in mitigating IR-induced effects on the cardio-thoracic system in both male and female wildtype mice exposed to upper body IR. Completing these studies could unveil sex-based disparities in redox metabolism and mitochondrial dysfunction, potentially offering targets for preventing or reducing IR-induced cardio-pulmonary toxicities. Rucosopasem might also emerge as a novel therapeutic approach for radiation mitigation.
