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

靶向细胞衰老以防止常见化疗药物阿霉素引起的加速血管老化

• 批准号: 10505896
• 负责人: DOUGLAS R SEALS
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505896
• 关键词: Advanced Glycosylation End Products; Age; Aging; Animals; Antioxidants; Arteries; Atherosclerosis; Biological Availability; Blood Vessels; Cancer Survivor; Cardiovascular Diseases; Carotid Arteries; Cause of Death; Cell Aging; Cell Culture Techniques; Cell Cycle Arrest; Cell physiology; Cells; Clinical; Collagen; Coupled; Data; Deposition; Development; Disease; Doxorubicin; Elastin; Elderly; Endothelial Cells; Endothelium; Event; Exposure to; Female; Fibrinogen; Genes; Genetic; Goals; Grant; Impairment; Inflammatory; Intervention; Malignant Neoplasms; Mechanics; Mediating; Mitochondria; Modeling; Modulus; Morbidity - disease rate; Mus; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Outcome; Oxidative Stress; Pathology; Patients; Pharmacology; Phenotype; Physiologic pulse; Physiological; Plasma; Prevention; Process; Production; Reactive Oxygen Species; Request for Proposals; Risk; Role; Small Interfering RNA; Source; Structural Protein; Superoxides; United States National Institutes of Health; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Woman; age related; arterial stiffness; base; cancer therapy; cardiovascular disorder risk; cardiovascular risk factor; cellular targeting; chemotherapeutic agent; chemotherapy; crosslink; heart function; improved; in vivo; insight; interest; male; mature animal; men; mortality; mouse model; new therapeutic target; novel; pre-clinical; preservation; prevent; response; senescence; therapeutic target; young adult

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.

项目摘要/摘要 增长年龄是心血管疾病（CVD）的主要危险因素。随着衰老的增加，CVD风险增加的风险是 通过血管功能障碍介导的主要介导的主要功能，包括血管内皮功能受损和 大型弹性动脉（主要是主动脉）增加了。这些血管功能的变化在很大程度上是 由于线粒体超氧化物的产生增加而导致的活性氧过多（ROS）， 减少血管舒张分子一氧化氮（NO）的生物利用度，并诱导结构性变化 动脉壁。但是，调节这些过程的上游事件尚不完全理解。细胞 衰老，一种大型细胞周期停滞的物理状态，再加上分泌 炎症因子（即，与感应相关的秘书表型[SASP]）最近已经是 由我们和其他人建立，是与年龄有关的血管功能障碍的关键机制。 有趣的是，接受阿霉素（DOXO）化学疗法接受癌症治疗的年轻人 具有血管功能障碍（例如，下层内皮功能和更大的主动脉僵硬），类似于甚至 比没有疾病的老年人观察到的要糟。此外，doxo-的机制 诱导的血管功能障碍类似于年龄增长的血管功能障碍，包括线粒体ROS和 降低无生物利用度。因此，Doxo化学疗法被视为加速血管衰老的模型， 但是，就像自然老化一样，管理这些蜂窝过程的上游机械事件尚未 我们假设细胞感应是预防的新型治疗靶点 和/或DOXO化疗治疗后加速血管衰老的治疗。 这项NIH探索/开发补助金（R21）申请的目的是响应NOT-CA-21-031 （了解癌症治疗对衰老轨迹的影响）是研究细胞的作用 普通化学治疗剂诱导的介导加速血管衰老中的感应 阿霉素（doxo）。 假设1：年轻成人DoxO治疗后体内感觉到感觉细胞的清除率 动物将通过抑制线粒体ROS生物活性来预防血管功能障碍，因此 没有生物利用度。由DOXO治疗的小鼠进行了“鼻溶液”干预措施 血管功能相似，在接受媒介物治疗的年轻小鼠中观察到的情况相似。 假设2：DOXO诱导的SASP激活将降低血管（内皮）细胞功能，这些功能 效果将通过激活细胞感应而介导。 可交付成果：这些研究的结果将提高我们对癌症影响的理解 对衰老结局的治疗，并为细胞感应作为一种新的治疗靶标提供了新的见解 减少Doxo处理的癌症存活中的血管功能障碍和CVD风险。