Doxorubicin cardiotoxicity and the protective effects of exercise

阿霉素心脏毒性和运动的保护作用

• 批准号: 10166985
• 负责人: Ashley Smuder
• 金额: $ 3.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166985
• 关键词: Anthracycline; Attenuated; Biological; Blood Vessels; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Carrier Proteins; Cell Death; Clinical; Consensus; Cytochrome c Reductase; Development; Doxorubicin; Endothelium; Event; Exercise; Foundations; Free Radicals; Future; Goals; Heart; Iron; Lead; Malignant Neoplasms; Mediating; Mitochondria; Molecular; Myocardial; Myocardial dysfunction; Oxidation-Reduction; Pathology; Permeability; Play; Prevalence; Prevention; Prevention strategy; Production; Risk Factors; Role; Solid Neoplasm; Testing; Therapeutic; Tight Junctions; Tissues; Toxic effect; Vascular Permeabilities; Xenobiotics; anti-cancer; cardiovascular disorder risk; chemotherapeutic agent; endurance exercise; exercise training; heart function; heart preservation; mitochondrial dysfunction; outcome forecast; prevent; protective effect; solute; translational study

PROJECT SUMMARY Doxorubicin (DOX) is a highly effective anticancer anthracycline used in the treatment of a wide variety of solid tumor malignancies. However, clinical use of this powerful chemotherapeutic is limited by the prevalence of irreversible cardiac tissue damage, which carries a poor prognosis and is often fatal. While efforts have been made to identify risk factors, develop less-toxic derivatives and detect subclinical toxicity earlier, there is currently no consensus on the best approach to prevent anthracycline-induced cardiomyopathy. Thus, further advances in the understanding of the molecular basis of DOX-induced pathology are needed to generate preventative strategies. DOX accumulates rapidly within cardiac tissue following exposure, where it preferentially localizes to the mitochondria and promotes free radical production through redox cycling with NADH dehydrogenase and iron cycling between Fe2+ and Fe3+. Elevated free radical production in the mitochondria can lead to severe damaging events resulting in cell death, and evidence suggests that prevention of mitochondrial dysfunction is sufficient to attenuate the cardiotoxic effects of DOX. Therefore, elucidating ways in which the mitochondrial accumulation of DOX can be reduced could result in the development of a therapeutic approach to mitigate the cardiotoxic effects of DOX. In this regard, we recently discovered that endurance exercise training prior to DOX treatment is sufficient to reduce the mitochondrial accumulation of DOX and preserve cardiac function. While the mechanisms responsible for the exercise-induced reduction in the levels of cardiac mitochondrial DOX are unknown, we hypothesize that activity-induced changes in the expression of xenobiotic transport proteins and/or changes in vascular tight junction integrity may play a role in mediating the entry of DOX into the cardiomyocytes. Therefore, the goal of this proposal is to establish the effects of exercise training on the expression of solute carrier transport proteins and on vascular permeability, and to determine if targeting these mechanisms has therapeutic potential to prevent DOX-induced cardiac dysfunction. We will accomplish this by testing the following specific aims: Specific Aim 1) will determine the effects of exercise and doxorubicin on the expression of solute carrier proteins in the heart; and Specific Aim 2) will determine if exercise-induced protection against DOX cardiotoxicity is related to changes in endothelial function and tight junction permeability.

项目摘要 多柔比星（DOX）是一种高效的抗癌蒽环类抗生素，用于治疗各种各样的固体肿瘤。 恶性肿瘤然而，这种强大的化疗药物的临床使用受到以下流行病的限制： 不可逆转的心脏组织损伤，预后不良，往往是致命的。虽然努力 为了识别风险因素，开发毒性较小的衍生物，并更早地检测亚临床毒性，目前 对于预防蒽环类药物引起的心肌病的最佳方法没有达成共识。因此，进一步的进展 在理解DOX诱导的病理学的分子基础上， 战略布局DOX在暴露后在心脏组织内迅速积累，在那里它优先定位于 线粒体和促进自由基的生产，通过氧化还原循环与NADH脱氢酶， 铁在Fe 2+和Fe 3+之间循环。线粒体中自由基产生的增加可导致严重的 破坏性事件导致细胞死亡，有证据表明，预防线粒体功能障碍是 足以减弱DOX的心脏毒性作用。因此，阐明线粒体 DOX的积累可以减少，这可能导致开发一种治疗方法来减轻 DOX的心脏毒性作用在这方面，我们最近发现，耐力运动训练之前，DOX 治疗足以减少DOX的线粒体积累并保护心脏功能。而 运动引起的心肌线粒体DOX水平降低的机制是 未知，我们假设活性诱导的外源性转运蛋白和/或 血管紧密连接完整性的变化可能在介导DOX进入心肌细胞中起作用。 因此，本研究的目的是建立运动训练对溶质表达的影响， 载体转运蛋白和血管通透性，并确定是否针对这些机制， 预防DOX诱导的心功能障碍的治疗潜力。我们将通过测试 具体目标1）将确定运动和阿霉素对表达的影响， 的溶质载体蛋白在心脏;和具体目标2）将确定是否运动诱导的保护， DOX心脏毒性与内皮功能和紧密连接通透性的变化有关。