Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice
Overexpression of catalase targeted to mitochondria improves neurovascular coupling responses in aged mice
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DOI：
10.1007/s11357-019-00111-0
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发表时间：
2019-10-23
期刊：
影响因子：
5.6
通讯作者：
Tarantini, Stefano
中科院分区：
文献类型：
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作者：
Csiszar, Anna;Yabluchanskiy, Andriy;Tarantini, Stefano
通过被称为神经血管耦合（NVC）的稳态机制，脑血流量（CBF）对神经元活动的即时调整对于维持正常的大脑功能具有重要作用。在高龄时，脑微血管内皮功能障碍会损害 NVC 反应，从而导致与年龄相关的认知能力下降。最近，我们发现，减少线粒体活性氧（ROS）产生的药物治疗可提供显着的神经血管保护，改善老年小鼠的 NVC 反应。过度表达位于线粒体的人过氧化氢酶（mCAT）的转基因小鼠可以免受与年龄相关的线粒体氧化应激的影响，并表现出与对几种与年龄相关的病理的抵抗力相关的长寿表型。本研究旨在检验以下假设：线粒体靶向的过氧化氢酶过度表达也能防止与年龄相关的 NVC 反应受损。为了实现这一目标，我们对老年（24 个月大）mCAT 小鼠的 NVC 反应进行了评估，并通过测量对侧胡须刺激引起的 CBF 反应（激光散斑对比成像）与年龄匹配的野生型小鼠和年轻对照小鼠进行比较。我们发现，线粒体中过氧化氢酶的过度表达导致老年小鼠的 NVC 改善，因为该反应保留了 NO 介导的（L-NAME 可抑制的）成分。因此，我们目前和之前的研究结果表明，增强线粒体抗氧化防御的干预措施可赋予显着的脑微血管保护作用，从而保留老年小鼠的 NVC 反应。我们的研究结果为线粒体靶向抗氧化剂作为预防与衰老相关的血管认知障碍的疗法的潜在用途提供了额外的概念验证。
Moment-to-moment adjustment of cerebral blood flow (CBF) to neuronal activity via the homeostatic mechanism known as neurovascular coupling (NVC) has an essential role in maintenance of normal brain function. In advanced age cerebromicrovascular endothelial dysfunction impairs NVC responses, which contribute to age-related cognitive decline. Recently, we have shown that pharmacological treatments that attenuate mitochondrial production of reactive oxygen species (ROS) provide significant neurovascular protection, improving NVC responses in aged mice. Transgenic mice that overexpress human catalase localized to the mitochondria (mCAT) are protected from age-related mitochondrial oxidative stress and exhibit a longevity phenotype associated with resistance to several age-related pathologies. The present study was designed to test the hypothesis that mitochondria-targeted overexpression of catalase also confers protection against age-related impairment of NVC responses. To achieve this goal, NVC responses were assessed in aged (24 months old) mCAT mice and compared with those in age-matched wild-type mice and young control mice by measuring CBF responses (laser speckle contrast imaging) evoked by contralateral whisker stimulation. We found that mitochondrial overexpression of catalase resulted in improved NVC in aged mice due to preserved NO-mediated (L-NAME inhibitable) component of the response. Thus, our present and previous findings demonstrate that interventions that boost mitochondrial antioxidative defenses confer significant cerebromicrovascular protective effects, which preserve NVC responses in aged mice. Our findings provide additional proof-of-concept for the potential use of mitochondria-targeted antioxidants as therapy for prevention of vascular cognitive impairment associated with aging.