Department of Physiology, University of Arizona, Tucson, Arizona, United States of America.
PLoS One. 2012;7(7):e41574. doi: 10.1371/journal.pone.0041574. Epub 2012 Jul 23.
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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.
最近，MicroRNAs（miR）和 AMP-kinase（AMPK）已成为心肌肥厚和心力衰竭发展中的重要参与者。我们假设，腺苷单磷酸激活酶（AMPK）途径的成分是受 miRs 靶向的，并且在病理性心脏应激期间改变 AMPK 信号转导。
方法/主要发现：我们使用肥厚型心肌病（HCM）的小鼠模型，证明了 miR-195 和 miR-451 在 HCM 心脏中的早期升高，其靶向 MO25，MO25/STRAD/LKB1 复合物的核心成分，作为 AMPK 的上游激酶。我们证明了 miR-195 和 -451 对 MO25 的功能靶向。进一步对 MO25 作为功能靶点的体外研究验证了这一假设，即在 C2C12 细胞中过表达 miR-195 会降低 MO25 的表达水平和下游 AMPK 信号（乙酰辅酶 A 羧化酶[ACC]的磷酸化和 AMPK 活性测定），类似于 C2C12 细胞中 siRNA 对 MO25 的敲低。在 60 天 R403Q HCM 雄性心脏中也测量到了类似的平行变化，这些心脏通过短期给予 AMPK 激动剂 AICAR 得到了挽救。
结论/意义：升高的 miR-195 靶向 HCM 进展中的 LKB1/AMPK 信号轴，并暗示其在 HCM 疾病进展中具有功能作用。miR-195 可能作为心脏病的潜在治疗剂或治疗靶点。
