Psychosocial Stress Exacerbates Doxorubicin-induced Cardiovascular Aging

项目摘要/摘要： 接受低剂量蒽环类药物(如阿霉素，DOX)的儿童会出现潜在的心脏毒性 并可因其他心血管危险因素而加重。心理社会压力是一种重要的心血管疾病 风险因素和儿童癌症幸存者的巨大负担。尽管观察性研究表明 心理社会压力与癌症幸存者心血管并发症的高发生率有关， 这种联系的机制尚未阐明。为了填补这一知识空白，我们开发了一种“两次成功” 青少年DOX诱发潜在心脏毒性的小鼠模型，这种毒性因心理社会压力而加剧。这个 本项目的总体目标是确定DOX/应激诱导的分子机制 并测试可以预防它的治疗方法。我们的初步数据显示暴露在 对幼年小鼠给予临床上相关的低剂量DOX(4 mg/kg/周，连续3周)激活心脏p38 丝裂原活化蛋白激酶(MAPK)和诱导细胞衰老的标志物。共同管理 多效性植物化学药物白藜芦醇与DOX一起抑制DOX激活的p38MAPK，并阻止DOX-MAPK。 潜在的心脏毒性。此外，在5周的恢复期后，接触DOX的小鼠表现出 加重心肌纤维化，增加衰老标记物p21和衰老的表达- 相关分泌模式(SASP)，当挑战一个经过验证的慢性心理社会压力模型时。 用ABT-263进行感觉神经溶解治疗可消除上述作用。中心假设是：心理社会压力会 通过p38/衰老加重DOX诱导的心血管衰老以诱发明显的心肌病 中介机制。在目标1中，我们将测试DOX(4毫克/公斤/周，连续3周)将激活的假设 依赖p38的心血管老化导致潜在的心脏毒性。DOX引起的心血管衰老将是 可被白藜芦醇和p38选择性抑制剂losmapimod阻止，并将被感觉剂逆转。 药物ABT-263。在目标2中，我们将检验以下假设：慢性心理社会压力(14天的感觉接触 有优势动物，每天10分钟的失败发作)将加剧DOX诱导的心血管 衰老导致明显的心肌病，白藜芦醇、洛斯帕米和ABT-263将限制这种作用。 在目标3中，我们将表征DOX/-白藜芦醇、洛斯帕米和ABT-263对心血管的影响 免疫活性EL4淋巴瘤肿瘤的功能和重塑，以及心血管老化的标志物 生老鼠。然后，我们将确定这些药物对阿昔洛韦化疗效益的影响 携带肿瘤的小鼠。这个项目是创新的，因为我们将采用一种新颖的“两击”鼠标模型 DOX/应激诱导的心肌病首次确定化学物质和应激物质之间的相互作用 心血管衰老中的心理社会应激源。这一点意义重大，因为它将建立心理社会压力。 作为加剧DOX诱导的心血管衰老的危险因素，并将使设计有效的 预防甚至逆转癌症幸存者化疗引起的心血管老化的治疗方法。

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.