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Int. J. Mol. Sci. 2018, 19(2), 522; https://doi.org/10.3390/ijms19020522

miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of Insulin-Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to Methylglyoxal

URT Genomics of Diabetes-IEOS, CNR & Department of Translational Medicine, Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy
These authors equally contributed to this study.
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Author to whom correspondence should be addressed.
Received: 2 February 2018 / Revised: 6 February 2018 / Accepted: 6 February 2018 / Published: 9 February 2018
(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)
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Abstract

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. View Full-Text
Keywords: miRNAs; endothelium; insulin resistance; diabetes mellitus; methylglyoxal miRNAs; endothelium; insulin resistance; diabetes mellitus; methylglyoxal
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Nigro, C.; Mirra, P.; Prevenzano, I.; Leone, A.; Fiory, F.; Longo, M.; Cabaro, S.; Oriente, F.; Beguinot, F.; Miele, C. miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of Insulin-Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to Methylglyoxal. Int. J. Mol. Sci. 2018, 19, 522.

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