Metformin treatment alleviates polycystic ovary syndrome by decreasing the expression of MMP-2 and MMP-9 via H19/miR-29b-3p and AKT/mTOR/autophagy signaling pathways
Metformin treatment alleviates polycystic ovary syndrome by decreasing the expression of MMP-2 and MMP-9 via H19/miR-29b-3p and AKT/mTOR/autophagy signaling pathways
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DOI：
10.1002/jcp.28594
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Zhang, Qinghua
中科院分区：
文献类型：
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作者：
Chen, Zhilan;Wei, Huafang;Zhang, Qinghua
在这项研究中，我们的目的是研究二甲双胍（MET）对基质金属蛋白酶（MMP）-2和MMP-9表达影响的分子途径。采用实时荧光定量PCR、Western blot和明胶酶谱法检测MET对MMP和AMPK信号通路的影响。此外，用miR-29 b-3 p/a乱序对照、H19/a阴性对照或MET/PBS处理HTOG细胞，以探索MET对MMP-2/MMP-9的抑制作用的潜在信号传导途径。建立多囊卵巢综合征（PCOS）大鼠模型，在体内验证MET的分子机制。MET抑制MMP-9/MMP-2和mTOR的表达，同时增加Akt和AMPK的表达，表明MET通过AMPK信号通路降低MMP的表达。H19/miR-29 b-3 p/MMP-9和H19/miR-29 b-3 p/MMP-2信号通路参与PCOS的发生，其中H19/miR-29 b-3 p和MMP-9/MMP-2/miR-29 b-3 p之间存在相互作用。此外，MET的施用抑制H19的表达，同时升高miR-29 b-3 p的表达。通过检测PCOS大鼠细胞或血清中H19和AMPK信号通路的活性，也证实了MET在PCOS中的作用。MET通过降低MMPs的表达在PCOS的治疗中表现出治疗作用。
In this study, we aimed to investigate the molecular pathway(s) underlying the effect of metformin (MET) on the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Real-time polymerase chain reaction, Western blot analysis, and gelatin zymography were used to assay the effects of MET on MMP and AMPK signaling pathways. In addition, HTOG cells were treated with miR-29b-3p/a scramble control, H19/a negative control, or MET/PBS to explore possible signaling pathway(s) underlying the inhibitory effect of MET on MMP-2/MMP-9. A rat model of polycystic ovary syndrome (PCOS) was also established to validate the molecular mechanism(s) of MET in vivo. The administration of MET suppressed the expression of MMP-9/MMP-2 and mTOR while increasing the expression of Akt and AMPK, indicating that MET reduced the expression of MMPs via the AMPK signaling pathway. Meanwhile, the H19/miR-29b-3p/MMP-9 and H19/miR-29b-3p/MMP-2 signaling pathways were implicated in PCOS, in which the interactions between H19/miR-29b-3p and MMP-9/MMP-2/miR-29b-3p were confirmed. Furthermore, the administration of MET suppressed the expression of H19 while elevating the expression of miR-29b-3p. And the role of MET in PCOS was also confirmed in vivo via examining the activity of H19 and AMPK signaling pathways in cell or serum samples collected from PCOS rats. MET exhibits a therapeutic effect in the treatment of PCOS by reducing the expression of MMPs.