Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25

Hao Chen, Gustavo M. Untiveros, Laurel A.K. McKee, Jessica Perez, Jing Li, Parker B. Antin, John P. Konhilas

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Background: 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.

Original languageEnglish (US)
Article numbere41574
JournalPloS one
Volume7
Issue number7
DOIs
StatePublished - Jul 23 2012
Externally publishedYes

Fingerprint

Adenylate Kinase
AMP-activated protein kinase
MicroRNAs
microRNA
Hypertrophic Cardiomyopathy
cardiomyopathy
phosphotransferases (kinases)
Phosphotransferases
Heart Failure
heart
adenosine monophosphate
therapeutics
acetyl-CoA carboxylase
Phosphorylation
Cardiomegaly
heart diseases
heart failure
Adenosine Monophosphate
small interfering RNA
hypertrophy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Chen, H., Untiveros, G. M., McKee, L. A. K., Perez, J., Li, J., Antin, P. B., & Konhilas, J. P. (2012). Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25. PloS one, 7(7), [e41574]. https://doi.org/10.1371/journal.pone.0041574

Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25. / Chen, Hao; Untiveros, Gustavo M.; McKee, Laurel A.K.; Perez, Jessica; Li, Jing; Antin, Parker B.; Konhilas, John P.

In: PloS one, Vol. 7, No. 7, e41574, 23.07.2012.

Research output: Contribution to journalArticle

Chen, H, Untiveros, GM, McKee, LAK, Perez, J, Li, J, Antin, PB & Konhilas, JP 2012, 'Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25', PloS one, vol. 7, no. 7, e41574. https://doi.org/10.1371/journal.pone.0041574
Chen, Hao ; Untiveros, Gustavo M. ; McKee, Laurel A.K. ; Perez, Jessica ; Li, Jing ; Antin, Parker B. ; Konhilas, John P. / Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25. In: PloS one. 2012 ; Vol. 7, No. 7.
@article{e4e18e1bed114d4a91b9d55ec47e51fa,
title = "Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25",
abstract = "Background: 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.",
author = "Hao Chen and Untiveros, {Gustavo M.} and McKee, {Laurel A.K.} and Jessica Perez and Jing Li and Antin, {Parker B.} and Konhilas, {John P.}",
year = "2012",
month = "7",
day = "23",
doi = "10.1371/journal.pone.0041574",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25

AU - Chen, Hao

AU - Untiveros, Gustavo M.

AU - McKee, Laurel A.K.

AU - Perez, Jessica

AU - Li, Jing

AU - Antin, Parker B.

AU - Konhilas, John P.

PY - 2012/7/23

Y1 - 2012/7/23

N2 - Background: 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.

AB - Background: 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.

UR - http://www.scopus.com/inward/record.url?scp=84864190840&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864190840&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0041574

DO - 10.1371/journal.pone.0041574

M3 - Article

C2 - 22844503

AN - SCOPUS:84864190840

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e41574

ER -