Project Summary/Abstract: Latent cardiotoxicity occurs in children who receive low doses of anthracyclines (e.g. doxorubicin, DOX) and can be exacerbated by other cardiovascular risk factors. Psychosocial stress is a significant cardiovascular risk factor and an enormous burden in childhood cancer survivors. Although observational studies demonstrate that psychosocial stress is associated with higher rates of cardiovascular complications in cancer survivors, the mechanism of this association has not been elucidated. To fill this gap in knowledge, we developed a ?two-hit? mouse model of juvenile DOX-induced latent cardiotoxicity that is exacerbated by psychosocial stress. The overall objectives of this project are to determine the molecular mechanisms of DOX/Stress-induced cardiomyopathy and to test treatments that can prevent it. Our preliminary data demonstrated that exposure of juvenile mice to a low, yet clinically relevant, dose of DOX (4 mg/kg/week for 3 weeks) activated cardiac p38 mitogen-activated protein kinase (MAPK) and induced markers of cellular senescence. Co-administration of the pleiotropic phytochemical resveratrol with DOX abrogated DOX-activated p38 MAPK and prevented DOX- induced latent cardiotoxicity. Additionally, after a 5-week recovery period, DOX-exposed mice manifested exaggerated myocardial fibrosis and increased expression of the senescence marker p21 and senescence- associated secretory pattern (SASP) when challenged with a validated model of chronic psychosocial stress. Senolytic therapy with ABT-263 abrogated these effects. The central hypothesis is: psychosocial stress will exacerbate DOX-induced cardiovascular aging to precipitate overt cardiomyopathy via a p38/senescence- mediated mechanism. In aim 1, we will test the hypothesis that DOX (4 mg/kg/week for 3 weeks) will activate p38-dependent cardiovascular aging leading to latent cardiotoxicity. DOX-induced cardiovascular aging will be prevented by resveratrol and by the p38 selective inhibitor losmapimod, and will be reversed by the senolytic drug ABT-263. In aim 2, we will test the hypothesis that chronic psychosocial stress (14-day sensory contact with a dominant animal, and daily 10-minute defeat episodes) will exacerbate DOX-induced cardiovascular aging leading to overt cardiomyopathy, an effect that will be limited by resveratrol, losmapimod, and ABT-263. In aim 3, we will characterize the effects of DOX +/- resveratrol, losmapimod, and ABT-263 on cardiovascular function and remodeling, and markers of cardiovascular aging in immunocompetent EL4 lymphoma tumor- bearing mice. Then, we will determine the effect of these agents on the chemotherapeutic benefit of DOX in the tumor-bearing mice. This project is innovative because we will employ a novel ?two-hit? mouse model of DOX/Stress-induced cardiomyopathy to determine, for the first time, the interplay between chemical and psychosocial stressors in cardiovascular aging. This is significant because it will establish psychosocial stress as a risk factor for exacerbating DOX-induced cardiovascular aging and will enable the design of effective therapies to prevent or even reverse chemotherapy-induced cardiovascular aging in cancer survivors.