title: The role of miR-190a in methylglyoxal-induced insulin resistance in endothelial cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Paola
authors.initials: P
authors.lastname: Mirra
authors.affiliation: 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.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nigro
authors.affiliation: 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.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Prevenzano
authors.affiliation: 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.
authors.forename: Teresa
authors.initials: T
authors.lastname: Procopio
authors.affiliation: 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.
authors.forename: Alessia
authors.initials: A
authors.lastname: Leone
authors.affiliation: 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.
authors.forename: Gregory Alexander
authors.initials: GA
authors.lastname: Raciti
authors.affiliation: Department of Medical and Surgical Sciences, University Magna-Graecia, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.affiliation: 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.
authors.forename: Michele
authors.initials: M
authors.lastname: Longo
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiory
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.affiliation: 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
mesh_terms: D000818:Animals; D002460:Cell Line; D003920:Diabetes Mellitus / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism*; D006019:Glycolysis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism*
chemical_list: D007328:Insulin; C546705:MIRN190 microRNA, mouse; D035683:MicroRNAs; D011765:Pyruvaldehyde; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Diabetes mellitus; Endothelium; Insulin resistance; Methylglyoxal; miRNAs