Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain
Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain
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DOI：
10.1038/sj.jcbfm.9600491
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发表时间：
2007-12-01
影响因子：
6.3
通讯作者：
Iadecola, Costantino
中科院分区：
文献类型：
--
作者：
Park, Laibaik;Anrather, Josef;Iadecola, Costantino
衰老与脑血管失调有关，这可能是老年人更容易发生缺血性中风和血管性认知障碍的原因。尽管人们早已知道氧化应激是导致脑血管功能障碍的原因，但产生活性氧（ROS）的酶系统尚未确定。在这项研究中，我们研究了产生超氧化物的酶 NADPH 氧化酶是否参与了衰老引起的神经血管调节的改变。通过激光多普勒血流测定法记录配备颅窗的麻醉 C57BL/6 小鼠（年龄 = 3、12 和 24 个月）的脑血流量 (CBF)。在 12 个月大的小鼠中，胡须刺激或内皮依赖性血管扩张剂乙酰胆碱和缓激肽引起的 CBF 增加分别减弱了 42%、36% 和 53%（P < 0.05）。相反，对一氧化氮供体 S-亚硝基-D-青霉胺或腺苷的反应并未减弱 (P > 0.05)。通过氢乙啶显微荧光检查评估，这些脑血管效应与神经元和脑血管中 ROS 产生的增加有关。 12 个月大小鼠中存在的脑血管损伤可被 ROS 清除剂 Mn (III) 四（4-苯甲酸）氯化卟啉或 NADPH 氧化酶肽抑制剂 gp91ds-tat 逆转，而在缺乏 NADPH 氧化酶 Nox2 亚基的小鼠中未观察到。这些发现证实 Nox2 是神经血管氧化应激的关键来源，介导与年龄增长相关的有害脑血管效应。
Aging is associated with cerebrovascular dysregulation, which may underlie the increased susceptibility to ischemic stroke and vascular cognitive impairment occurring in the elder individuals. Although it has long been known that oxidative stress is responsible for the cerebrovascular dysfunction, the enzymatic system(s) generating the reactive oxygen species (ROS) have not been identified. In this study, we investigated whether the superoxide-producing enzyme NADPH oxidase is involved in alterations of neurovascular regulation induced by aging. Cerebral blood flow (CBF) was recorded by laser-Doppler flowmetry in anesthetized C57BL/6 mice equipped with a cranial window (age = 3, 12, and 24 months). In 12- month-old mice, the CBF increases evoked by whisker stimulation or by the endothelium-dependent vasodilators acetylcholine and bradykinin were attenuated by 42, 36, and 53%, respectively (P < 0.05). In contrast, responses to the nitric oxide donor S-nitroso-D-penicillamine or adenosine were not attenuated (P > 0.05). These cerebrovascular effects were associated with increased production of ROS in neurons and cerebral blood vessels, assessed by hydroethidine microfluorography. The cerebrovascular impairment present in 12-month-old mice was reversed by the ROS scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride or by the NADPH oxidase peptide inhibitor gp91ds-tat, and was not observed in mice lacking the Nox2 subunit of NADPH oxidase. These findings establish Nox2 as a critical source of the neurovascular oxidative stress mediating the deleterious cerebrovascular effects associated with increasing age.