Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25.
Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25.
复制标题
DOI：
10.1371/journal.pone.0041574
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Konhilas JP
中科院分区：
文献类型：
--
作者：
Chen H;Untiveros GM;McKee LA;Perez J;Li J;Antin PB;Konhilas JP
近年来，MicroRNA（miR）和AMPK（AMPK）在心肌肥厚和心力衰竭的发生发展中发挥了重要作用。我们假设，在病理性心脏应激过程中，腺苷一磷酸激活激酶（AMPK）通路的组分被miR靶向并改变AMPK信号传导。使用肥厚型心肌病（HCM）小鼠模型，我们证明了HCM心脏中miR-195和miR-451的早期升高，其靶向MO 25，MO 25是MO 25/STRAD/LKB 1复合物的中心组分，作为AMPK的上游激酶。我们显示了miR-195和-451对MO 25的功能靶向作用。MO 25作为功能靶标的进一步体外研究验证了这一假设，其中C2 C12细胞中miR-195的过表达敲低了MO 25表达水平和下游AMPK信号传导（乙酰辅酶A羧化酶[ACC]的磷酸化和AMPK活性测定），类似于通过siRNA敲低C2 C12细胞中的MO 25。在60天的R403 Q HCM雄性心脏中测量了平行的变化，这些心脏通过短期施用AMPK激动剂AICAR来挽救。升高的miR-195靶向HCM进展中的LKB 1/AMPK信号传导轴，并暗示在HCM疾病进展中的功能作用。MiR-195可以作为心脏病的潜在治疗剂或治疗靶点。
Recently, MicroRNAs (miR) and AMP-kinase (AMPK) have emerged as prominent players in the development of cardiac hypertrophy and heart failure. We hypothesized that components of the adenosine monophosphate-activated kinase (AMPK) pathway are targeted by miRs and alter AMPK signaling during pathological cardiac stress. Using a mouse model of hypertrophic cardiomyopathy (HCM), we demonstrated early elevation of miR-195 and miR-451 in HCM hearts, which targets MO25, a central component of the MO25/STRAD/LKB1 complex that acts as an upstream kinase for AMPK. We show functional targeting of MO25 by miR-195 and -451. Further in vitro interrogation of MO25 as a functional target validated this hypothesis where over-expression of miR-195 in C2C12 cells knocked down MO25 expression levels and downstream AMPK signaling (phosphorylation of Acetyl CoA carboxylase [ACC] and AMPK activity assay), similar to MO25 knockdown in C2C12 cells by siRNA. Parallel changes were measured in 60 day R403Q HCM male hearts that were rescued by short-term administration of AICAR, an AMPK agonist. Elevated miR-195 targets the LKB1/AMPK signaling axis in HCM progression and implicates a functional role in HCM disease progression. MiR-195 may serve as potential therapeutics or therapeutic targets for heart disease.
登录
查看更多内容
影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1152/ajpheart.2001.280.3.h1136
发表时间：
2001-03-01
影响因子：
4.8
作者：
Olsson, MC;Palmer, BM;Moore, RL
通讯作者：
Moore, RL
影响因子：
37.8
作者：
Dyck, Jason R. B.;Hopkins, Teresa A.;Lopaschuk, Gary D.
通讯作者：
Lopaschuk, Gary D.
影响因子：
2.5
作者：
Bell, GW;Yatskievych, TA;Antin, PB
通讯作者：
Antin, PB
影响因子：
11.4
作者：
Boudeau, J;Baas, AF;Alessi, DR
通讯作者：
Alessi, DR