FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic Focal Stroke in Diabetic db/db Male Mice via Cerebrovascular PPARγ Activation
FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic Focal Stroke in Diabetic db/db Male Mice via Cerebrovascular PPARγ Activation
复制标题
FGF21 通过脑血管 PPARγ 激活，防止糖尿病 db/db 雄性小鼠缺血性局灶性中风后血脑屏障严重破坏
DOI：
10.3390/ijms21030824
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Wang, Xiaoying
中科院分区：
文献类型：
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作者：
Jiang, Yinghua;Lin, Li;Wang, Xiaoying
重组成纤维细胞生长因子 21 (rFGF21) 已被证明对改善 2 型糖尿病 (T2DM) 中风小鼠的长期神经系统结果具有显着益处。在这里，我们测试了这样的假设：rFGF21 通过脑微血管内皮中的过氧化物酶体增殖物激活受体 γ (PPAR γ) 激活来保护 T2DM 小鼠免受中风后血脑屏障 (BBB) 损伤。在本研究中，我们使用 T2DM 小鼠的远端中脑闭塞（dMCAO）模型以及培养的人脑微血管内皮细胞（HBMEC）进行高血糖和炎症损伤。我们检测到中风后 24 小时，脑组织中 PPAR γ DNA 结合活性显着降低，脑微血管中 BBB 连接蛋白和 PPAR γ 靶向基因 CD36 和 FABP4 的 mRNA 水平显着降低。与瘦对照小鼠相比，缺血性中风在 T2DM 小鼠中风两天后导致大量 BBB 渗漏。重要的是，中风后 6 小时开始施用 rFGF21 可以显着预防所有异常变化。我们的体外实验结果还表明，rFGF21 通过以 FGFR1 激活和 PPAR γ 活性升高依赖性方式上调连接蛋白表达，防止高血糖加白细胞介素 (IL)-1 fi 诱导的跨内皮通透性。我们的数据表明，rFGF21 对糖尿病中风后急性 BBB 渗漏具有很强的保护作用，这部分是通过增加 PPAR γ DNA 结合活性和 BBB 连接复合物蛋白的 mRNA 表达来介导的。结合我们之前的研究，rFGF21 可能是治疗糖尿病中风的有希望的候选者。
Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently beneficial for improving long-term neurological outcomes in type 2 diabetes mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects against poststroke blood-brain barrier (BBB) damage in T2DM mice via peroxisome proliferator-activated receptor gamma (PPAR gamma) activation in cerebral microvascular endothelium. We used the distal middle cerebral occlusion (dMCAO) model in T2DM mice as well as cultured human brain microvascular endothelial cells (HBMECs) subjected to hyperglycemic and inflammatory injury in the current study. We detected a significant reduction in PPAR gamma DNA-binding activity in the brain tissue and mRNA levels of BBB junctional proteins and PPAR gamma-targeting gene CD36 and FABP4 in cerebral microvasculature at 24 h after stroke. Ischemic stroke induced a massive BBB leakage two days after stroke in T2DM mice compared to in their lean controls. Importantly, all abnormal changes were significantly prevented by rFGF21 administration initiated at 6 h after stroke. Our in vitro experimental results also demonstrated that rFGF21 protects against hyperglycemia plus interleukin (IL)-1 fi-induced transendothelial permeability through upregulation of junction protein expression in an FGFR1 activation and PPAR gamma activity elevation-dependent manner. Our data suggested that rFGF21 has strong protective effects on acute BBB leakage after diabetic stroke, which is partially mediated by increasing PPAR gamma DNA-binding activity and mRNA expression of BBB junctional complex proteins. Together with our previous investigations, rFGF21 might be a promising candidate for treating diabetic stroke.