MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway.
MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway.
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MiR-139-5p 通过靶向磷酸二酯酶 4D 激活 cAMP/PKA/CREB 信号通路，具有抗抑郁样作用
DOI：
10.21037/atm-21-5149
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发表时间：
2021-10
影响因子：
--
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Huang P;Wei S;Luo M;Tang Z;Lin Q;Wang X;Luo M;He Y;Wang C;Wei D;Xia C;Xu J
磷酸二酯酶4D （PDE4D）抑制剂是治疗抑郁症的常用药物，但其副作用严重降低了其疗效。PDE4D是miR-139-5p的下游靶mRNA。因此，我们研究了海马miR-139-5p的功能获得和功能丧失对抑郁样行为、PDE4D的表达水平和海马神经发生的影响。采用生物信息学分析筛选差异基因。采用实时定量聚合酶链反应（qRT-PCR）和荧光素酶报告基因法证实miR-139-5p与PDE4D之间的关系。使用MiR-139-5p模拟物、MiR-139-5p抑制剂或miR-NC来探索MiR-139-5p在HT-22细胞中的功能。我们通过注射aav进一步探讨了miR-139-5p在体内的作用。采用Elisa、western blotting和荧光原位杂交（FISH）检测CRC组织中miR-139-5p和PDE4D的表达。在这里，我们发现PDE4D信使RNA （mRNA）是microRNA (miR)-139-5p的直接靶点，miR -139-5p在慢性超轻度应激（CUMS）诱导的抑郁症小鼠模型中下调。此外，在体外实验中，miR-139-5p模拟物抑制了HT-22细胞中PDE4D的表达，但促进了磷酸化的环amp反应元件结合蛋白（p-CREB）和脑源性神经营养因子（BDNF）的表达。有趣的是，腺相关病毒(AAV)-miR-139-5p下调了小鼠对应激诱导的抑郁样行为的易感性。AAV-miR-139-5p抑制小鼠海马细胞PDE4D，增加环磷酸腺苷（cAMP）、p-CREB和BDNF的表达水平，刺激小鼠海马神经发生。我们的研究结果表明，miR-139-5p通过靶向PDE4D发挥抗抑郁药的作用，从而调节cAMP/蛋白激酶A (PKA)/CREB/BDNF通路来改善抑郁症。
Phosphodiesterase 4D (PDE4D) inhibitor is commonly used to treat depression, but side effects seriously decrease its efficacy. PDE4D was a downstream target mRNA of miR-139-5p. Therefore, we examined the effects of hippocampal miR-139-5p gain- and loss-of-function on depression-like behaviors, the expression level of PDE4D, and hippocampus neurogenesis. Bioinformatic analyses were carried out to to screen differential genes. Quantitative real-time polymerase chain reaction (qRT-PCR) and luciferase reporter assay were used to confirm the relationship between miR-139-5p and PDE4D. MiR-139-5p mimics, miR-139-5p inhibitor, or miR-NC were used to explore the function of miR-139-5p in HT-22 cells. We further explored the role of miR-139-5p in vivo using AAV-injection. Elisa, western blotting, and fluorescence in situ hybridization (FISH) were used to detect the expression of miR-139-5p and PDE4D in CRC tissues. Here, we showed that PDE4D messenger RNA (mRNA) was a direct target of microRNA (miR)-139-5p, which was downregulated in a chronic ultra-mild stress (CUMS)-induced depression mouse model. Moreover, in experiments in vitro, miR-139-5p mimic repressed PDE4D expression in HT-22 cells, but promoted phosphorylated cyclic-AMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. Interestingly, adeno-associated virus (AAV)-miR-139-5p downregulated susceptibility to stress-induced depression-like behaviors in mice. AAV-miR-139-5p suppressed PDE4D in mouse hippocampal cells, increasing expression level of cyclic adenosine monophosphate (cAMP), p-CREB, and BDNF, and stimulating mouse hippocampal neurogenesis. Our findings suggested that miR-139-5p acted like an antidepressant by targeting PDE4D, thereby regulating the cAMP/protein kinase A (PKA)/CREB/BDNF pathway to improve depression.
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