Fibrinogen in mice cerebral microvessels induces blood-brain barrier dysregulation with aging via a dynamin-related protein 1-dependent pathway.
Fibrinogen in mice cerebral microvessels induces blood-brain barrier dysregulation with aging via a dynamin-related protein 1-dependent pathway.
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DOI：
10.1007/s11357-023-00988-y
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发表时间：
2024-02
期刊：
影响因子：
5.6
通讯作者：
Busija, David W.
中科院分区：
文献类型：
--
作者：
Chandra, Partha K.;Selvam, Manesh Kumar Panner;Castorena-Gonzalez, Jorge A.;Rutkai, Ibolya;Sikka, Suresh C.;Mostany, Ricardo;Busija, David W.
关键词：
我们之前报道的证据表明，衰老过程中的氧化应激导致小鼠脑皮质微血管（MVs：末端小动脉、毛细血管和小静脉）的不良蛋白质谱变化，影响mRNA/蛋白质稳定性、基底膜完整性和ATP合成能力。作为我们之前研究的延伸，我们还发现，随着年龄的增长，构成血脑屏障（BBB）和调节线粒体质量控制的蛋白质在小鼠皮质MVs中也显著减少。有趣的是，神经炎症蛋白纤维蛋白原（Fgn）在小鼠脑MVs中增加，这与临床报道的血浆Fgn浓度随着年龄的增长而逐渐增加相一致。在这项研究中，蛋白-蛋白相互作用网络分析表明，Fgn的高表达与衰老小鼠皮质MVs中BBB-和线粒体裂变/融合相关蛋白的表达下调有关。为了研究Fgn的作用机制，我们观察到2 mg/mL或更高浓度的人血浆Fgn改变了原代人脑微血管内皮细胞（HBMECs）的细胞形态，诱导细胞毒性，并增加了血脑屏障通透性。原代hbmec中血脑屏障紧密连接蛋白随着人血浆Fgn浓度的升高而显著降低。同样，fgnn处理的hbmec中磷酸化动力蛋白相关蛋白1 （pDRP1）和其他线粒体裂变/融合相关蛋白的表达也显著降低。有趣的是，shRNA敲低DRP1 (h)导致hbmec中BBB-和线粒体裂变/融合相关蛋白的减少。我们的研究结果表明，升高的Fgn下调DRP1，导致线粒体依赖性的脑微血管内皮和血脑屏障功能障碍。在线版本包含补充材料，可在10.1007/s11357-023-00988-y获得。
We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, and ATP synthesis capacity in mice. As an extension of our previous study, we also found that proteins which comprise the blood–brain barrier (BBB) and regulate mitochondrial quality control were also significantly decreased in the mice’s cortical MVs with aging. Interestingly, the neuroinflammatory protein fibrinogen (Fgn) was increased in mice brain MVs, which corresponds with clinical reports indicating that the plasma Fgn concentration increased progressively with aging. In this study, protein–protein interaction network analysis indicated that high expression of Fgn is linked with downregulated expression of both BBB- and mitochondrial fission/fusion–related proteins in mice cortical MVs with aging. To investigate the mechanism of Fgn action, we observed that 2 mg/mL or higher concentration of human plasma Fgn changed cell morphology, induced cytotoxicity, and increased BBB permeability in primary human brain microvascular endothelial cells (HBMECs). The BBB tight junction proteins were significantly decreased with increasing concentration of human plasma Fgn in primary HBMECs. Similarly, the expression of phosphorylated dynamin-related protein 1 (pDRP1) and other mitochondrial fission/fusion–related proteins were also significantly reduced in Fgn-treated HBMECs. Interestingly, DRP1 knockdown by shRNA(h) resulted in the reduction of both BBB- and mitochondrial fission/fusion–related proteins in HBMECs. Our results suggest that elevated Fgn downregulates DRP1, leading to mitochondrial-dependent endothelial and BBB dysfunction in the brain microvasculature. The online version contains supplementary material available at 10.1007/s11357-023-00988-y.
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影响因子：
8.3
作者：
Doll DN;Hu H;Sun J;Lewis SE;Simpkins JW;Ren X
通讯作者：
Ren X
影响因子：
3.5
作者：
Chen H;Chan DC
通讯作者：
Chan DC
影响因子：
64.5
作者：
Chen H;Vermulst M;Wang YE;Chomyn A;Prolla TA;McCaffery JM;Chan DC
通讯作者：
Chan DC
DOI：
10.1177/0271678x21999553
发表时间：
2021-09
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Chandra PK;Cikic S;Baddoo MC;Rutkai I;Guidry JJ;Flemington EK;Katakam PV;Busija DW
通讯作者：
Busija DW
影响因子：
8.8
作者：
Cui, Yaxiong;Wang, Yanxiao;Yang, Xiao
通讯作者：
Yang, Xiao