Targeting cellular senescence to prevent accelerated vascular aging induced by the common chemotherapeutic agent doxorubicin

项目摘要/摘要 高龄是心血管疾病(CVD)的主要危险因素。随着年龄的增长，心血管疾病风险增加 主要由血管功能障碍，包括血管内皮功能受损和 大的弹性动脉(主要是主动脉)硬化增加。这些血管功能的变化在很大程度上 由于线粒体超氧化物产生增加而产生过多的活性氧物种(ROS)， 这会降低血管扩张分子一氧化氮(NO)的生物利用度，并导致血管结构的变化 动脉壁。然而，调控这些过程的上游事件并不完全清楚。蜂窝 衰老，一种主要是永久性的细胞周期停滞的生理状态，伴随着促肾上腺皮质激素的分泌 炎症因子(即与衰老相关的分泌表型[SASP])最近被 我们和其他人建立了一个与年龄相关的血管功能障碍的关键机制。 有趣的是，接受过阿霉素(Doxo)化疗的癌症治疗的年轻人 有血管功能障碍(例如，内皮功能降低和主动脉僵硬)，类似或甚至 比在没有疾病的老年人身上观察到的更糟糕。此外，DOXO-的潜在机制- 引起的血管功能障碍类似于那些年龄较大的人，包括更大的线粒体ROS和 降低NO的生物利用度。因此，Doxo化疗被视为加速血管老化的模型， 但就像自然衰老一样，控制这些细胞过程的上游机械事件并没有 已经建立了。我们假设细胞衰老是预防的新的治疗靶点。 和/或Doxo化疗后加速血管老化的治疗。 根据NOT-CA-21-031申请NIH探索性/开发补助金(R21)的目的 (了解癌症治疗对衰老轨迹的影响)是为了研究细胞的作用 常见化疗药物诱导血管加速衰老过程中的衰老 阿霉素(Doxo)。 假设1：年轻成人服用DOXO后体内衰老细胞的清除(衰老) 动物将通过抑制线粒体ROS生物活性和随之而来的 保存无生物利用度。给予DOXO治疗的小鼠进行“感觉化”干预后，将有 血管功能类似于在接受车辆治疗的年轻成年小鼠中观察到的情况。 假设2：DOXO诱导的SASP激活会降低血管(内皮)细胞功能，这些 这些效应将通过激活细胞衰老来实现。 成果：这些研究的结果将促进我们对癌症影响的理解 对衰老结局的治疗和对细胞衰老作为新的治疗靶点的新见解 以降低接受多西他滨治疗的癌症幸存者的血管功能障碍和心血管风险。

PROJECT SUMMARY/ABSTRACT Advancing age is the primary risk factor for cardiovascular diseases (CVD). Increased CVD risk with aging is mediated primarily by vascular dysfunction, including impaired vascular endothelial function and increased large elastic artery (primarily aortic) stiffening. These changes in vascular function are largely due to excessive reactive oxygen species (ROS) as a result of increased mitochondrial superoxide production, which reduce bioavailability of the vasodilatory molecule nitric oxide (NO) and induce structural changes in the arterial wall. However, the upstream events regulating these processes are incompletely understood. Cellular senescence, a physiological state of largely-permanent cell cycle arrest coupled with the secretion of pro- inflammatory factors (i.e., the senescence-associated secretory phenotype [SASP]), has recently been established by us and others to be a key mechanism of age-related vascular dysfunction. Interestingly, young adults who have undergone cancer treatment with doxorubicin (DOXO) chemotherapy have vascular dysfunction (e.g., lower endothelial function and greater aortic stiffness), similar to or even worse than what is observed in older adults without disease. Moreover, the mechanisms underlying DOXO- induced vascular dysfunction are similar to those with advancing age, including greater mitochondrial ROS and lower NO bioavailability. As such, DOXO chemotherapy is viewed as a model of accelerated vascular aging, but like with naturally aging, the upstream mechanistic events governing these cellular processes have not been established. We hypothesize that cellular senescence is a novel therapeutic target for the prevention and/or treatment of accelerated vascular aging following DOXO chemotherapy treatment. The purpose of this NIH Exploratory/Development grant (R21) application in response to NOT-CA-21-031 (Understanding the effects of cancer treatment on aging trajectories) is to investigate the role of cellular senescence in mediating accelerated vascular aging induced by the common chemotherapeutic agent doxorubicin (DOXO). Hypothesis 1: Clearance of senescent cells (senolysis) in vivo following DOXO treatment in young adult animals will prevent vascular dysfunction via suppression of mitochondrial ROS bioactivity and consequent preservation of NO bioavailability. DOXO-treated mice administered a “senolytic” intervention will have vascular function similar what is observed in young adult mice that received vehicle treatment. Hypothesis 2: DOXO-induced activation of the SASP will reduce vascular (endothelial) cell function and these effects will be mediated by activation of cellular senescence. Deliverables: The results of these studies will advance our understanding of the effects of cancer treatment on aging outcomes and provide new insight into cellular senescence as a novel therapeutic target to reduce vascular dysfunction and CVD risk in DOXO-treated cancer survivors.