Mitochondria-targeted antioxidant therapy in age-related arterial stiffness

项目摘要 年龄增长是心血管疾病发展的主要危险因素，而这主要是 可归因于血管功能障碍的发展，包括大弹性动脉僵硬增加。 目前的人口趋势预测，老年人的人口将大幅增加。因此，一顶 生物医学研究的重点是确定保护血管功能并保持低水平的策略 动脉硬化随着年龄的增长而增加，因为这可能有助于预防、减少或延缓心血管疾病的发展。 与年龄相关的动脉僵硬涉及动脉的主要结构变化，但其背后的机制 人们对结构性变化的理解还不完全。一个令人信服的假设是，多余的线粒体- 血管系统中衍生的活性氧物种(MtROS)可能起到关键作用。随着年龄的增长和 MtROS的增加会导致mtROS诱导的线粒体功能障碍的恶性循环，这可能会促进 通过慢性炎症信号的诱导，与年龄相关的动脉硬化。因此，减少线粒体 氧化应激和功能障碍可能是治疗随着年龄增长的动脉僵硬的一个有前途的靶点。 该项目的中心假设是线粒体靶向抗氧化剂(MitoQ)可能是一种新的 通过减少mtROS治疗和/或预防年龄相关性动脉僵硬的治疗选择--和 随之而来的是线粒体功能障碍和血管系统中的炎症信号。 具体目标1：在治疗前、治疗中和治疗后评估大弹性动脉僵硬。 在饮用水中加入线粒体抗氧化剂。老年老鼠将在短时间前和短时间后接受测试- 为期4周的线粒体抗氧化剂治疗，以检验治疗将减少动脉的假设 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，以确定潜在的治疗，以防止僵硬增加随着年龄增长(目标1.2)。 具体目标2：确定动脉结构成分和炎症标志物的变化 衰老和MitoQ治疗的小鼠(目标2.1)；全面评估线粒体功能的变化 (包括对呼吸功能的新评估)在衰老和MitoQ治疗的小鼠的动脉中 (目标2.2)；以及研究线粒体氧化应激和炎症在介导动脉粥样硬化中的作用 通过评估幼年和老年小鼠动脉的固有僵硬和结构变化来评估 使用mtROS产生和/或炎症的调节剂进行治疗(目标2.3)。 总体而言，该项目将：a)确定线粒体抗氧化剂对治疗和/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，以 支持将线粒体抗氧化剂疗法转化为人类；以及c)提供对 MtROS在与年龄相关的大弹性动脉僵硬形成中的作用及其机制 衰老和/或抗氧化剂治疗可能改变血管线粒体生理学。

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.