Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex-dependent manner.
Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex-dependent manner.
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大脑中的铁不平衡会对大脑功能产生负面影响。随着年龄的增长，大脑中的铁含量增加，导致脑损伤和神经系统疾病。随着年龄的增长，脑血管系统的变化可能会增加铁进入脑实质，导致铁过载及其有害后果。内皮衰老已成为脑血管系统年龄相关变化的重要因素。有证据表明，铁超载可诱导培养细胞系的衰老。重要的是，与雄性相比，来自女性人类和小鼠的细胞通常显示出增强的衰老相关表型。因此，我们假设与来自老年雄性的脑内皮细胞（CEC）相比，来自老年雌性小鼠的脑内皮细胞（CEC）更容易受到铁诱导的衰老的影响。我们发现，老年雌性小鼠（而非雄性小鼠）在长期接受柠檬酸铁（FC）治疗时表现出认知缺陷，其大脑和脑血管系统表现出衰老相关表型。我们还发现，当用FC处理时，来自老年雌性小鼠的CEC原代培养物（而非雄性来源的CEC）表现出衰老相关表型。我们发现，跨膜受体Robo4在脑血管和培养的初级CEC来自老年雌性小鼠，与那些从雄性小鼠相比，下调。我们发现Robo4下调有助于增强对FC诱导衰老的脆弱性。因此，我们的研究将Robo4下调确定为CEC原代培养中铁过载诱导的衰老的驱动因素，以及脑血管损伤和脑功能障碍的潜在风险因素。与老年雄性小鼠相比，老年雌性小鼠的脑功能更容易受到长期补充铁的柠檬酸铁（FC）的影响。在从老年雌性小鼠分离的培养的原代脑内皮细胞（CEC）中，FC加重了衰老相关表型，但在老年雄性小鼠的CEC中未加重。与雄性相比，Robo4在老年雌性小鼠的血管系统中下调，并且来自老年雄性小鼠的CEC在Robo4下调后变得对FC更敏感。
Iron imbalance in the brain negatively affects brain function. With aging, iron levels increase in the brain and contribute to brain damage and neurological disorders. Changes in the cerebral vasculature with aging may enhance iron entry into the brain parenchyma, leading to iron overload and its deleterious consequences. Endothelial senescence has emerged as an important contributor to age‐related changes in the cerebral vasculature. Evidence indicates that iron overload may induce senescence in cultured cell lines. Importantly, cells derived from female human and mice generally show enhanced senescence‐associated phenotype, compared with males. Thus, we hypothesize that cerebral endothelial cells (CEC) derived from aged female mice are more susceptible to iron‐induced senescence, compared with CEC from aged males. We found that aged female mice, but not males, showed cognitive deficits when chronically treated with ferric citrate (FC), and their brains and the brain vasculature showed senescence‐associated phenotype. We also found that primary culture of CEC derived from aged female mice, but not male‐derived CEC, exhibited senescence‐associated phenotype when treated with FC. We identified that the transmembrane receptor Robo4 was downregulated in the brain vasculature and in cultured primary CEC derived from aged female mice, compared with those from male mice. We discovered that Robo4 downregulation contributed to enhanced vulnerability to FC‐induced senescence. Thus, our study identifies Robo4 downregulation as a driver of senescence induced by iron overload in primary culture of CEC and a potential risk factor of brain vasculature impairment and brain dysfunction. The brain function of aged female mice is more vulnerable to chronic administration of iron supplement ferric citrate (FC), compared with aged male mice. Senescence‐associated phenotype is exacerbated by FC in cultured primary cerebral endothelial cells (CEC) isolated from aged female mice, but not in CEC from aged male mice. Robo4 is downregulated in the cerebrovasculature of aged female mice, versus males, and CEC from aged male mice become more susceptible to FC after Robo4 downregulation.
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影响因子：
3.7
作者：
Lee CT;Lee CC;Wu MJ;Chiu YW;Leu JG;Wu MS;Peng YS;Wu MS;Tarng DC
通讯作者：
Tarng DC
影响因子：
3.7
作者：
Heringa, S. M.;van den Berg, E.;Biessels, G. J.
通讯作者：
Biessels, G. J.
影响因子：
4.3
作者：
Li M;Ji C;Xuan W;Chen W;Lv Y;Liu T;You Y;Gao F;Zheng Q;Shao J
通讯作者：
Shao J
梓醇对 RhoA/ROCK-2 通路的抑制和紧密连接蛋白的上调可抑制脂多糖诱导的血脑屏障通透性破坏
DOI：
10.3390/molecules23092371
发表时间：
2018-09-17
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Feng S;Zou L;Wang H;He R;Liu K;Zhu H
通讯作者：
Zhu H
影响因子：
37.8
作者：
Durik M;Kavousi M;van der Pluijm I;Isaacs A;Cheng C;Verdonk K;Loot AE;Oeseburg H;Bhaggoe UM;Leijten F;van Veghel R;de Vries R;Rudez G;Brandt R;Ridwan YR;van Deel ED;de Boer M;Tempel D;Fleming I;Mitchell GF;Verwoert GC;Tarasov KV;Uitterlinden AG;Hofman A;Duckers HJ;van Duijn CM;Oostra BA;Witteman JC;Duncker DJ;Danser AH;Hoeijmakers JH;Roks AJ
通讯作者：
Roks AJ