Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline.
Nox2 underpins microvascular inflammation and vascular contributions to cognitive decline.
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Nox2支持微血管炎症和血管对认知能力下降的贡献。
DOI：
10.1177/0271678x221077766
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发表时间：
2022-07
期刊：
影响因子：
--
通讯作者：
Horsburgh K
中科院分区：
文献类型：
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作者：
Alfieri A;Koudelka J;Li M;Scheffer S;Duncombe J;Caporali A;Kalaria RN;Smith C;Shah AM;Horsburgh K
慢性微血管炎症和氧化应激是支持白色疾病和血管性认知障碍（VCI）的相互关联的机制。一种提议的介质是烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶2（Nox 2），其是脑中活性氧（ROS）的主要来源。为了评估Nox 2在VCI中的作用，我们研究了由双侧颈动脉狭窄（BCAS）诱导的具有白色病理和认知障碍的易处理模型。在BCAS后，将具有Nox2基因缺失（Nox2 KO）的小鼠与野生型（WT）进行比较。WT小鼠中持续BCAS超过12周诱导Nox 2表达、微血管炎症和氧化损伤的指数，沿着白色病理学，最终导致显著的认知障碍，这些都受到Nox 2基因缺失的保护。WT小鼠BCAS后神经血管偶联受损，Nox2 KO小鼠恢复。Nox 2缺乏可改善WT小鼠BCAS后血管中化学引诱物介质、细胞粘附分子和内皮活化因子表达的增加。临床相关性通过在患有脑血管疾病的人类死后受试者中增加的血管Nox 2和微血管炎症指数来证实。我们的研究结果支持Nox2活性作为VCI的关键决定因素，其靶向可能对脑血管疾病具有治疗益处。
Chronic microvascular inflammation and oxidative stress are inter-related mechanisms underpinning white matter disease and vascular cognitive impairment (VCI). A proposed mediator is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2), a major source of reactive oxygen species (ROS) in the brain. To assess the role of Nox2 in VCI, we studied a tractable model with white matter pathology and cognitive impairment induced by bilateral carotid artery stenosis (BCAS). Mice with genetic deletion of Nox2 (Nox2 KO) were compared to wild-type (WT) following BCAS. Sustained BCAS over 12 weeks in WT mice induced Nox2 expression, indices of microvascular inflammation and oxidative damage, along with white matter pathology culminating in a marked cognitive impairment, which were all protected by Nox2 genetic deletion. Neurovascular coupling was impaired in WT mice post-BCAS and restored in Nox2 KO mice. Increased vascular expression of chemoattractant mediators, cell-adhesion molecules and endothelial activation factors in WT mice post-BCAS were ameliorated by Nox2 deficiency. The clinical relevance was confirmed by increased vascular Nox2 and indices of microvascular inflammation in human post-mortem subjects with cerebral vascular disease. Our results support Nox2 activity as a critical determinant of VCI, whose targeting may be of therapeutic benefit in cerebral vascular disease.