miR-191 suppresses angiogenesis by activation of NF-κB signaling
miR-191 suppresses angiogenesis by activation of NF-κB signaling
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miR-191通过激活NF-κB信号通路抑制血管生成
DOI：
10.1096/fj.201601263r
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发表时间：
2017-08-01
期刊：
影响因子：
4.8
通讯作者：
Laschke, Matthias W.
中科院分区：
文献类型：
--
作者：
Gu, Yuan;Ampofo, Emmanuel;Laschke, Matthias W.
microRNAs（miRNAs）是多种生物过程的强有力的调节因子。然而，大多数miRNA在血管生成中的功能仍然难以捉摸。在这项研究中，我们确定了miR-191- 5 p（miR-191）作为血管发育的有效抑制剂。用miR-191模拟物（miR-191 m）转染人真皮微血管内皮细胞抑制其增殖、迁移和管形成。此外，与对照组相比，miR-191 m转染的小鼠主动脉环的血管出芽显著减少。转染miR-191抑制剂（miR-191 i）可诱导促血管生成效应。miR-191 m和-191i的抗血管生成和促血管生成活性在体内得到进一步证实。另外的分子生物学分析显示，miR-191 m通过上调p65的mRNA表达来激活NF-κ B信号传导。miR-191还增加了抗血管生成因子p21和金属蛋白酶组织抑制剂-1的mRNA水平，并降低了促血管生成因子eNOS和基质金属蛋白酶-1和-9的表达。用Bay 11-7082阻断NF-kB活化逆转了miR-191 m的抗血管生成作用。这些发现表明，miR-191通过激活NF-κ B信号通路有效抑制血管生成。
MicroRNAs (miRNAs) are powerful regulators of diverse biologic processes. However, the function of most miRNAs in angiogenesis remains elusive. In this study, we identified miR-191-5p (miR-191) as a potent inhibitor of blood vessel development. Transfection of human dermal microvascular endothelial cells with miR-191 mimic (miR-191m) inhibited their proliferation, migration, and tube formation. Moreover, vascular sprouting of miR-191m-transfected mouse aortic rings was significantly reduced when compared with controls. Transfection with miR-191 inhibitor (miR-191i) induced proangiogenic effects. The anti-and proangiogenic activities of miR-191m and -191i were further demonstrated in vivo. Additional molecular biologic analyses revealed that miR-191m activates NF-kappa B signaling by up-regulating the mRNA expression of p65. miR-191 also increased the mRNA levels of the antiangiogenic factors p21 and tissue inhibitor of metalloproteinase-1 and reduced the expression of the proangiogenic factors eNOS and matrix metalloproteinase-1 and -9. Blockade of NF-kB activation with Bay 11-7082 reversed the antiangiogenic effects of miR-191m. These findings indicate that miR-191 effectively suppresses angiogenesis by activation of the NF-kB signaling pathway.