BACE2 deficiency impairs expression and function of endothelial nitric oxide synthase in brain endothelial cells.
BACE2 deficiency impairs expression and function of endothelial nitric oxide synthase in brain endothelial cells.
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DOI：
10.1111/jnc.15929
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发表时间：
2023-09
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
β位点淀粉样蛋白前体蛋白(APP)-切割酶2 （BACE2）在脑血管内皮中高表达。值得注意的是，BACE2是来自阿尔茨海默病患者的脑血管内皮中最下调的基因之一。本研究旨在确定BACE2在控制内皮型一氧化氮合酶（eNOS）表达和功能中的作用。小干扰RNA （BACE2siRNA）基因下调人脑微血管内皮细胞（BMECs）中BACE2可显著降低eNOS的表达，使eNOS在苏氨酸残基Thr495位点磷酸化，从而导致一氧化氮（NO）的产生减少。BACE2siRNA还能抑制APP的表达，减少可溶性APPα (sAPPα)的产生和释放。相反，腺病毒介导的APP过表达增加了eNOS的表达。与这些观察结果一致，纳米摩尔浓度的sAPPα和APP 17mer肽（来源于sAPPα）增强了eNOS的表达。进一步分析发现，γ-氨基丁酸B型受体亚基1和k<s:1> ppel样因子2可能是BACE2/APP/ sapp α-诱导eNOS上调的下游分子靶点。与培养的人内皮研究一致，bace2缺陷小鼠的脑动脉中乙酰胆碱依赖性松弛和环GMP的基础生成受损。我们提出在脑血管中，BACE2可能作为血管保护蛋白起作用。
Beta-site amyloid precursor protein (APP)-cleaving enzyme 2 (BACE2) is highly expressed in cerebrovascular endothelium. Notably, BACE2 is one of the most downregulated genes in cerebrovascular endothelium derived from patients with Alzheimer’s disease. The present study was designed to determine the role of BACE2 in control of expression and function of endothelial nitric oxide synthase (eNOS). Genetic downregulation of BACE2 in human brain microvascular endothelial cells (BMECs) with small interfering RNA (BACE2siRNA) significantly decreased expression of eNOS and elevated levels of eNOS phosphorylated at threonine residue Thr495, thus leading to reduced production of nitric oxide (NO). BACE2siRNA also suppressed expression of APP, and decreased production and release of soluble APPα (sAPPα). In contrast, adenovirus-mediated overexpression of APP increased expression of eNOS. Consistent with these observations, nanomolar concentrations of sAPPα and APP 17mer peptide (derived from sAPPα) augmented eNOS expression. Further analysis established that γ-aminobutyric acid type B receptor subunit 1 and Küppel-like factor 2 may function as downstream molecular targets significantly contributing to BACE2/APP/sAPPα-induced up regulation of eNOS. In agreement with studies on cultured human endothelium, endothelium-dependent relaxations to acetylcholine and basal production of cyclic GMP were impaired in cerebral arteries of BACE2-deficient mice. We propose that in brain vessels, BACE2 may function as a vascular protective protein.
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影响因子：
11
作者：
Alić I;Goh PA;Murray A;Portelius E;Gkanatsiou E;Gough G;Mok KY;Koschut D;Brunmeir R;Yeap YJ;O'Brien NL;Groet J;Shao X;Havlicek S;Dunn NR;Kvartsberg H;Brinkmalm G;Hithersay R;Startin C;Hamburg S;Phillips M;Pervushin K;Turmaine M;Wallon D;Rovelet-Lecrux A;Soininen H;Volpi E;Martin JE;Foo JN;Becker DL;Rostagno A;Ghiso J;Krsnik Ž;Šimić G;Kostović I;Mitrečić D;LonDownS Consortium;Francis PT;Blennow K;Strydom A;Hardy J;Zetterberg H;Nižetić D
通讯作者：
Nižetić D
影响因子：
11
作者：
Donev, R.;Newall, A.;Thome, J.;Sheer, D.
通讯作者：
Sheer, D.
影响因子：
15.1
作者：
Abdul-Hay SO;Sahara T;McBride M;Kang D;Leissring MA
通讯作者：
Leissring MA
影响因子：
11
作者：
Chen, Xingyong;Chen, Ling;Lin, Geng;Wang, Zhengjun;Kodali, Mahesh C.;Li, Mingqi;Chen, Huimin;Lebovitz, Sarah G.;Ortyl, Tyler C.;Li, Lexiao;Ismael, Saifudeen;Singh, Purnima;Malik, Kafait U.;Ishrat, Tauheed;Zhou, Fu-Ming;Zheng, Wei;Liao, Francesca-Fang
通讯作者：
Liao, Francesca-Fang
影响因子：
64.8
作者：
Dimmeler, S;Fleming, I;Zeiher, AM
通讯作者：
Zeiher, AM