PMID- 29425121
OWN - NLM
STAT- MEDLINE
DCOM- 20180808
LR  - 20181113
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 19
IP  - 2
DP  - 2018 Feb 9
TI  - miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of 
      Insulin-Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to 
      Methylglyoxal.
LID - 10.3390/ijms19020522 [doi]
LID - 522
AB  - Evidence has been provided linking microRNAs (miRNAs) and diabetic complications, 
      by the regulation of molecular pathways, including insulin-signaling, involved in 
      the pathophysiology of vascular dysfunction. Methylglyoxal (MGO) accumulates in 
      diabetes and is associated with cardiovascular complications. This study aims to 
      analyze the contribution of miRNAs in the MGO-induced damaging effect on insulin 
      responsiveness in mouse aortic endothelial cells (MAECs). miRNA modulation was 
      performed by transfection of specific miRNA mimics and inhibitors in MAECs, 
      treated or not with MGO. miRNA-target protein levels were evaluated by Western 
      blot. PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulation by 
      miR-214 was tested by luciferase assays and by the use of a target protector 
      specific for miR-214 on PHLPP2-3'UTR. This study reveals a 4-fold increase of 
      PHLPP2 in MGO-treated MAECs. PHLPP2 levels inversely correlate with miR-214 
      modulation. Moreover, miR-214 overexpression is able to reduce PHLPP2 levels in 
      MGO-treated MAECs. Interestingly, a direct regulation of PHLPP2 is proved to be 
      dependent by miR-214. Finally, the inhibition of miR-214 impairs the 
      insulin-dependent Akt activation, while its overexpression rescues the insulin 
      effect on Akt activation in MGO-treated MAECs. In conclusion, this study shows 
      that PHLPP2 is a target of miR-214 in MAECs, and identifies miR-214 
      downregulation as a contributing factor to MGO-induced endothelial 
      insulin-resistance.
FAU - Nigro, Cecilia
AU  - Nigro C
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      cecilia.nigro@alice.it.
FAU - Mirra, Paola
AU  - Mirra P
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      paolamirra.lib@libero.it.
FAU - Prevenzano, Immacolata
AU  - Prevenzano I
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      imma.prevenzano@libero.it.
FAU - Leone, Alessia
AU  - Leone A
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      aleleone86@libero.it.
FAU - Fiory, Francesca
AU  - Fiory F
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      francesca-976@libero.it.
FAU - Longo, Michele
AU  - Longo M
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      mi_longo@libero.it.
FAU - Cabaro, Serena
AU  - Cabaro S
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      serenacabaro@gmail.com.
FAU - Oriente, Francesco
AU  - Oriente F
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      foriente@unina.it.
FAU - Beguinot, Francesco
AU  - Beguinot F
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      beguino@unina.it.
FAU - Miele, Claudia
AU  - Miele C
AD  - URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, 
      Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy. 
      c.miele@ieos.cnr.it.
LA  - eng
PT  - Journal Article
DEP - 20180209
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Insulin)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn214 microRNA, mouse)
RN  - 722KLD7415 (Pyruvaldehyde)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.3.16 (PHLPP2 protein, mouse)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
SB  - IM
MH  - Animals
MH  - Aorta/cytology/metabolism
MH  - Cells, Cultured
MH  - Endothelial Cells/drug effects/metabolism
MH  - Endothelium, Vascular/cytology/drug effects/*metabolism
MH  - Insulin/metabolism
MH  - Mice
MH  - MicroRNAs/genetics/metabolism
MH  - Phosphoprotein Phosphatases/*genetics/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyruvaldehyde/toxicity
MH  - Signal Transduction
PMC - PMC5855744
OTO - NOTNLM
OT  - diabetes mellitus
OT  - endothelium
OT  - insulin resistance
OT  - methylglyoxal
OT  - miRNAs
COIS- The authors declare no conflict of interest.
EDAT- 2018/02/10 06:00
MHDA- 2018/08/09 06:00
PMCR- 2018/02/01
CRDT- 2018/02/10 06:00
PHST- 2018/02/02 00:00 [received]
PHST- 2018/02/06 00:00 [revised]
PHST- 2018/02/06 00:00 [accepted]
PHST- 2018/02/10 06:00 [entrez]
PHST- 2018/02/10 06:00 [pubmed]
PHST- 2018/08/09 06:00 [medline]
PHST- 2018/02/01 00:00 [pmc-release]
AID - ijms19020522 [pii]
AID - ijms-19-00522 [pii]
AID - 10.3390/ijms19020522 [doi]
PST - epublish
SO  - Int J Mol Sci. 2018 Feb 9;19(2):522. doi: 10.3390/ijms19020522.