Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
Research Service, Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC, USA.
FASEB J. 2020 May;34(5):6808-6823. doi: 10.1096/fj.201901318R. Epub 2020 Apr 2.
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor and uncoupler of nitric oxide synthase, has gained attention as a risk factor for cardiac disease, metabolic syndrome, and cerebrovascular disease. In this study, we investigated the role of systemic ADMA overburden in cerebromicrovascular pathology associated with cognitive dysfunction using APPSwDI transgenic mice expressing human β-amyloid precursor protein Swedish (Tg-SwDI), a model of cerebrovascular β-amyloidosis. To induce systemic overburden of ADMA, Tg-SwDI mice were treated with a daily dose of exogenous ADMA. ADMA treatment resulted in elevated ADMA levels in the blood and brain of Tg-SwDI mice. ADMA treatment induced the brain nitrosative stress and inflammation as well as enhanced the brain Aβ deposition and cognitive impairment in Tg-SwDI mice. However, ADMA treatment had no such effects on wild type mice. ADMA treatment also exacerbated brain microvascular pathology in Tg-SwDI mice as observed by increased blood-brain barrier dysfunction, loss of tight junction proteins, increased endothelial stress fibers, and decreased microvessel density in the brain. In addition, similar observations were made in cultured human brain microvessel endothelial cells, where ADMA in the presence of VEGF-induced endothelial cell signaling for F-actin stress fiber inducing endothelial barrier dysfunction. Overall, these data document the potential role of ADMA in the cognitive pathology under conditions of cerebrovascular β-amyloidosis.
不对称二甲基精氨酸（ADMA）是一种内源性的一氧化氮合酶抑制剂和解偶联剂，已成为心脏病、代谢综合征和脑血管病的危险因素。在这项研究中，我们使用表达人类β-淀粉样前体蛋白瑞典突变（Tg-SwDI）的 APPsweDI 转基因小鼠研究了系统性 ADMA 过载在与认知功能障碍相关的脑微血管病理学中的作用，Tg-SwDI 是一种脑血管β-淀粉样蛋白病的模型。为了诱导 ADMA 的系统性过载，Tg-SwDI 小鼠接受外源性 ADMA 的每日剂量治疗。ADMA 处理导致 Tg-SwDI 小鼠的血液和大脑中的 ADMA 水平升高。ADMA 处理诱导脑硝化应激和炎症，以及增强 Tg-SwDI 小鼠的脑 Aβ 沉积和认知障碍。然而，ADMA 处理对野生型小鼠没有这种作用。ADMA 处理还加剧了 Tg-SwDI 小鼠的脑微血管病理学，如血脑屏障功能障碍增加、紧密连接蛋白丢失、内皮应激纤维增加和脑微血管密度降低。此外，在培养的人脑微血管内皮细胞中也观察到类似的观察结果，其中 ADMA 在 VEGF 存在下诱导内皮细胞信号转导，导致 F-肌动蛋白应激纤维诱导内皮屏障功能障碍。总的来说，这些数据证明了 ADMA 在脑血管β-淀粉样蛋白病情况下认知病理学中的潜在作用。
