Psychosocial Stress Exacerbates Doxorubicin-induced Cardiovascular Aging

项目概要/摘要： 接受低剂量蒽环类药物（如多柔比星、DOX）的儿童发生潜在心脏毒性 并可能因其他心血管风险因素而加剧。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发生率较高有关， 这种关联的机制尚未阐明。为了填补这一知识空白，我们开发了一种“二击” 幼年DOX诱导的潜在心脏毒性的小鼠模型，其由心理社会应激加剧。的 本项目的总体目标是确定DOX/应激诱导的 我们的初步数据表明，暴露于心肌病和测试治疗，可以防止它。 幼龄小鼠接受低剂量但临床相关剂量的DOX（4 mg/kg/周，持续3周）激活心脏p38 丝裂原活化蛋白激酶（MAPK）和诱导的细胞衰老标志物。共同施用 多效性植物化学物质白藜芦醇与DOX一起消除了DOX激活的p38 MAPK，并阻止了DOX- 诱发潜在心脏毒性。此外，在5周的恢复期后，暴露于DOX的小鼠表现出 心肌纤维化加重，衰老标志物p21和衰老- 相关的分泌模式（SASP）的挑战时，验证模型的慢性心理社会压力。 ABT-263的衰老清除疗法消除了这些作用。核心假设是：心理社会压力会 加剧DOX诱导的心血管衰老，通过p38/衰老促进明显的心肌病， 中介机制。在目标1中，我们将检验DOX（4 mg/kg/周，持续3周）将激活 p38依赖性心血管衰老导致潜在的心脏毒性。DOX诱导的心血管衰老将是 由白藜芦醇和p38选择性抑制剂losmapimod阻止，并将被衰老清除剂逆转。 ABT-263药物在目标2中，我们将检验慢性心理社会压力（14天的感觉接触） 与占优势的动物，每天10分钟的失败事件）将加剧DOX诱导的心血管疾病 衰老导致明显的心肌病，白藜芦醇、losmapimod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、losmapimod和ABT-263对心血管系统的作用。 功能和重塑，以及免疫活性EL 4淋巴瘤肿瘤的心血管衰老标志物- 产鼠然后，我们将确定这些药物对DOX化疗益处的影响， 荷瘤小鼠。这个项目是创新的，因为我们将采用一种新颖的“两击”小鼠模型， DOX/应激诱导的心肌病，首次确定化学和 心血管老化中的心理社会压力源。这是很重要的，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风险因素， 预防甚至逆转癌症幸存者化疗诱导的心血管衰老的治疗。

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.