Mitochondria-targeted antioxidant therapy in age-related arterial stiffness

线粒体靶向抗氧化疗法治疗年龄相关动脉僵硬度

• 批准号: 8718365
• 负责人: Rachel Gioscia-Ryan
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718365
• 关键词: Advanced Glycosylation End Products; Age; Aging; Antioxidants; Arteries; Biomedical Research; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic; Collagen; Complement; Data; Development; Elastin; Elderly; Electron Spin Resonance Spectroscopy; Event; Functional disorder; Future; Health; Heat shock proteins; Human; Immunohistochemistry; Inflammation; Inflammatory; Intervention; Intervention Studies; Investigation; Laboratories; Measures; Mechanical Stress; Mediating; Mentors; Metabolic; Mitochondria; Mus; Oxidative Stress; Physiologic pulse; Physiological; Physiology; Placebo Control; Play; Population; Prevention; Process; Production; Reactive Oxygen Species; Research; Research Personnel; Research Priority; Resolution; Respiratory physiology; Risk Factors; Role; Signal Transduction; Testing; Therapeutic Effect; Time; Training; Translations; Treatment Efficacy; Vascular Diseases; Vasomotor; Work; age related; antioxidant therapy; arterial stiffness; cardiovascular disorder risk; career; clinical application; drinking water; experience; in vivo; inflammatory marker; insight; male; middle age; mitochondrial dysfunction; mortality; mouse model; novel; novel therapeutics; post-doctoral training; pre-clinical; prevent; public health relevance; respiratory; skills; stress protein; therapeutic target; trend

Project Summary Advancing age is a primary risk factor for the development of cardiovascular disease, and this is primarily attributable to the development of vascular dysfunction, including increased large elastic artery stiffness. Current demographic trends predict a major increase in the population of older adults. Therefore, a top biomedical research priority is to identify strategies that preserve vascular function and maintain low arterial stiffness with advancing age, as this may help prevent, reduce, or delay the development of CVD. Age-related arterial stiffness involves major structural changes to arteries, but mechanisms underlying these structural changes are incompletely understood. A compelling hypothesis is that excess mitochondria- derived reactive oxygen species (mtROS) in the vasculature may play a key role. With advancing age an increase in mtROS drives a vicious cycle of mtROS-induced mitochondrial dysfunction which may promote age-related arterial stiffening via induction of chronic inflammatory signaling. Thus, reducing mitochondrial oxidative stress and dysfunction may be a promising therapeutic target for arterial stiffness with aging. The central hypothesis of this project is that a mitochondria-targeted antioxidant (MitoQ) may be a novel therapeutic option for treating and/or preventing age-related arterial stiffness by reducing mtROS--and consequent mitochondrial dysfunction and inflammatory signaling-in the vasculature. Specific Aim 1: To assess large elastic artery stiffness before, during, and following treatment with mitochondrial antioxidants administered in the drinking water. Old mice will be tested before and after short- term (4 weeks) mitochondrial antioxidant therapy to test the hypothesis that treatment will reduce arterial stiffness (Aim 1.1), whereas middle-aged mice will be tested before, during and after long-term (9 months) therapy to determine the potential for treatment to prevent increases in stiffness with advancing age (Aim 1.2). Specific Aim 2: To determine changes in structural components and markers of inflammation in arteries of mice with aging and MitoQ treatment (Aim 2.1); to comprehensively assess changes in mitochondrial function (including novel assessment of respiratory function) in the arteries of mice with aging and MitoQ treatment (Aim 2.2); and to examine the role of mitochondrial oxidative stress and inflammation in mediating arterial stiffness by assessing intrinsic stiffness and structural changes in arteries from young and old mice following treatment with modulators of mtROS production and/or inflammation (Aim 2.3). Overall, this project will: a) establish the efficacy of mitochondrial antioxidants for the treatment and/or prevention of age-related stiffening of large elastic arteries; b) provide the necessary pre-clinical evidence to support the translation of mitochondrial antioxidant therapy to humans; and c) provide novel insight into the role of mtROS in the development of age-related large elastic artery stiffness, and the mechanisms whereby aging and/or antioxidant treatment may alter vascular mitochondrial physiology.

项目摘要 年龄增长是心血管疾病发展的主要危险因素，这主要是 这可归因于血管功能障碍的发展，包括大动脉弹性硬度的增加。 目前的人口趋势预测，老年人口将大幅增加。因此，顶部 生物医学研究的优先事项是确定保护血管功能和维持低 动脉硬化随着年龄的增长，因为这可能有助于预防，减少或延迟CVD的发展。 动脉硬化相关的动脉僵硬涉及动脉的主要结构变化，但这些变化的机制 结构变化还不完全清楚。一个令人信服的假设是过量的线粒体- 血管系统中衍生的活性氧（mtROS）可能起关键作用。随着年龄的增长， 线粒体ROS的增加驱动线粒体ROS诱导的线粒体功能障碍的恶性循环， 年龄相关的动脉硬化通过诱导慢性炎症信号。因此，减少线粒体 氧化应激和功能障碍可能是随着年龄增长的动脉硬化的有希望的治疗靶点。 该项目的中心假设是，一种靶向抗氧化剂（MitoQ）可能是一种新的抗氧化剂。 通过减少mtROS治疗和/或预防年龄相关动脉硬化的治疗选择-和 随之而来的线粒体功能障碍和炎症信号-在脉管系统中。 具体目的1：在治疗前、治疗期间和治疗后评估大弹性动脉僵硬度 线粒体抗氧化剂在饮用水中的管理。老年小鼠将在短- 长期（4周）线粒体抗氧化剂治疗，以检验治疗将减少动脉粥样硬化的假设。 僵硬（目标1.1），而中年小鼠将在长期（9个月）之前、期间和之后进行测试 治疗，以确定治疗的潜力，以防止随着年龄的增长僵硬增加（目标1.2）。 具体目标2：确定动脉中结构成分和炎症标志物的变化， 衰老和MitoQ治疗的小鼠（目的2.1）;全面评估线粒体功能的变化 （包括呼吸功能的新评估） (Aim 2.2）;并检查线粒体氧化应激和炎症在介导动脉粥样硬化中的作用。 通过评估年轻和老年小鼠动脉的固有硬度和结构变化， 用mtROS产生和/或炎症的调节剂治疗（目的2.3）。 总的来说，该项目将：a）确定线粒体抗氧化剂用于治疗和/或 预防与年龄相关的大弹性动脉硬化; B）提供必要的临床前证据， 支持将线粒体抗氧化剂疗法转化为人类;以及c）提供对线粒体抗氧化剂疗法的新见解。 线粒体活性氧在年龄相关性大弹性动脉僵硬发展中的作用及其机制 衰老和/或抗氧化剂治疗可能会改变血管线粒体生理学。