Role of microRNA29b in blood-brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism
Role of microRNA29b in blood-brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism
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DOI：
10.1038/jcbfm.2014.74
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发表时间：
2014-07-01
影响因子：
6.3
通讯作者：
Tyagi, Neetu
中科院分区：
文献类型：
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作者：
Kalani, Anuradha;Kamat, Pradip K.;Tyagi, Neetu
虽然血脑屏障（BBB）的完整性是由内皮细胞，连接蛋白和神经胶质血管网络的串扰，BBB通透性背后的表观遗传机制在很大程度上是未知的。我们首次报道了miR 29 b介导的BBB调节，这是一种新的BBB完整性机制。我们假设miR 29 b通过调节DNMT 3b来调节BBB功能障碍，从而调节金属蛋白酶的水平，金属蛋白酶可以吃掉膜和连接蛋白，导致血管渗漏。此外，使用5 '-氮杂胞苷（5'-aza）来测试其对BBB渗透性的功效。通过使用同型半胱氨酸建立血脑屏障破坏模型，并且在模型中，通过使用microRNA RT 2-qPCR阵列鉴定miR 29 b受影响最大。MiR 29 b模拟物和抑制剂也证实了miR 29 b调节DNMT 3b和MMP 9的水平。在具有高脑血管渗透性的高同型半胱氨酸血症胱硫醚-β-合酶缺陷（CBS+/-）小鼠中，与野生型（WT）小鼠相比，miR 29 b水平也高。有趣的是，5 '-aza通过降低miR 29 b的表达来改善BBB通透性。总之，我们的数据表明miR 29 b通过DNMT 3b和MMP 9介导了BBB功能障碍的调节。它还增强了microRNA作为未来表观遗传疗法的候选物在改善BBB完整性中的用途。
Although blood-brain barrier (BBB) integrity is maintained by the cross-talk of endothelial cells, junction proteins, and neurogliovascular network, the epigenetic mechanisms behind BBB permeability are largely unknown. We are reporting for the first time miR29b-mediated regulation of BBB, which is a novel mechanism underlying BBB integrity. We hypothesize that miR29b regulates BBB dysfunction by regulating DNMT3b, which consequently regulates the levels of metalloproteinases, that can eat up the membrane and junction proteins leading to leaky vasculature. In addition, 5'-azacytidine (5'-aza) was used to test its efficacy on BBB permeability. Blood-brain barrier disruption model was created by using homocysteine, and in the models miR29b was identified to be most affected, by using microRNA RT2-qPCR array. MiR29b mimics and inhibitors also confirmed that miR29b regulates the levels DNMT3b and MMP9. In hyperhomocysteinemic cystathionine-beta-synthase deficient (CBS+/-) mice with high brain vessel permeability, miR29b levels were also high as compared with wild-type (WT) mice. Interestingly, 5'-aza improved BBB permeability by decreasing the expression of miR29b. In conclusion, our data suggested miR29b-mediated regulation of BBB dysfunction through DNMT3b and MMP9. It also potentiates the use of microRNAs as candidates for future epigenetic therapies in the improvement of BBB integrity.