PMID- 27864140 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20191210 IS - 0925-4439 (Print) IS - 0925-4439 (Linking) VI - 1863 IP - 2 DP - 2017 Feb TI - The role of miR-190a in methylglyoxal-induced insulin resistance in endothelial cells. PG - 440-449 LID - S0925-4439(16)30300-3 [pii] LID - 10.1016/j.bbadis.2016.11.018 [doi] AB - Methylglyoxal (MGO) is a reactive dicarbonyl produced as by-product of glycolysis, and its formation is heightened in hyperglycaemia. MGO plasma levels are two-fold to five-fold increased in diabetics and its accumulation promotes the progression of vascular complications. Impairment of endothelium-derived nitric oxide represents a common feature of endothelial dysfunction in diabetics. We previously demonstrated that MGO induces endothelial insulin resistance. Increasing evidence shows that high glucose and MGO modify vascular expression of several microRNAs (miRNAs), suggesting their potential role in the impairment of endothelial insulin sensitivity. The aim of the study is to investigate whether miRNAs may be involved in MGO-induced endothelial insulin resistance in endothelial cells. MGO reduces the expression of miR-190a both in mouse aortic endothelial cells (MAECs) and in aortae from mice knocked-down for glyoxalase-1. miR-190a inhibition impairs insulin sensitivity, whereas its overexpression prevents the MGO-induced insulin resistance in MAECs. miR-190a levels are not affected by the inhibition of ERK1/2 phosphorylation. Conversely, ERK1/2 activation is sustained by miR-190a inhibitor and the MGO-induced ERK1/2 hyper-activation is reduced by miR-190a mimic transfection. Similarly, protein levels of the upstream KRAS are increased by both MGO and miR-190a inhibitor, and these levels are reduced by miR-190a mimic transfection. Interestingly, silencing of KRAS is able to rescue the MGO-impaired activation of IRS1/Akt/eNOS pathway in response to insulin. In conclusion, miR-190a down-regulation plays a role in MGO-induced endothelial insulin resistance by increasing KRAS. This study highlights miR-190a as new candidate for the identification of strategies aiming at ameliorating vascular function in diabetes. CI - Copyright (c) 2016 Elsevier B.V. All rights reserved. FAU - Mirra, Paola AU - Mirra P AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Nigro, Cecilia AU - Nigro C AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Prevenzano, Immacolata AU - Prevenzano I AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Procopio, Teresa AU - Procopio T AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Leone, Alessia AU - Leone A AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Raciti, Gregory Alexander AU - Raciti GA AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Andreozzi, Francesco AU - Andreozzi F AD - Department of Medical and Surgical Sciences, University Magna-Graecia, Catanzaro, Italy. FAU - Longo, Michele AU - Longo M AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Fiory, Francesca AU - Fiory F AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Beguinot, Francesco AU - Beguinot F AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Miele, Claudia AU - Miele C AD - URT of the Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy; Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. Electronic address: c.miele@ieos.cnr.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161115 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 RN - 0 (Insulin) RN - 0 (MIRN190 microRNA, mouse) RN - 0 (MicroRNAs) RN - 722KLD7415 (Pyruvaldehyde) RN - EC 3.6.5.2 (Hras protein, mouse) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM MH - Animals MH - Cell Line MH - Diabetes Mellitus/metabolism MH - *Down-Regulation MH - Endothelial Cells/*metabolism MH - Glycolysis MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Insulin/*metabolism MH - *Insulin Resistance MH - Mice MH - MicroRNAs/*genetics MH - Proto-Oncogene Proteins p21(ras)/metabolism MH - Pyruvaldehyde/*metabolism OTO - NOTNLM OT - Diabetes mellitus OT - Endothelium OT - Insulin resistance OT - Methylglyoxal OT - miRNAs EDAT- 2016/11/20 06:00 MHDA- 2018/12/12 06:00 CRDT- 2016/11/20 06:00 PHST- 2016/06/08 00:00 [received] PHST- 2016/10/17 00:00 [revised] PHST- 2016/11/14 00:00 [accepted] PHST- 2016/11/20 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2016/11/20 06:00 [entrez] AID - S0925-4439(16)30300-3 [pii] AID - 10.1016/j.bbadis.2016.11.018 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Basis Dis. 2017 Feb;1863(2):440-449. doi: 10.1016/j.bbadis.2016.11.018. Epub 2016 Nov 15.