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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

基本信息

批准号：
10684719
负责人：
DOUGLAS R SEALS
金额：
$ 23.48万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
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/10684719
关键词：
Acceleration Advanced Glycosylation End Products Age Aging Animals Antioxidants Aorta 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 Elasticity Elastin Elderly Endothelial Cells Endothelium Event Exposure to Female 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 Phenotype Physiologic pulse Physiological Plasma Prevention Process Production Reactive Oxygen Species Request for Proposals Risk Risk Reduction 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 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 pharmacologic pre-clinical preservation prevent response senescence therapeutic target young adult

项目摘要

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.