Leone, Alessia (2017) The role of Methylglyoxal in the impairment of angiogenic process in endothelial cells. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: The role of Methylglyoxal in the impairment of angiogenic process in endothelial cells
Creators:
CreatorsEmail
Leone, Alessiaaleleone86@hotmail.com
Date: 10 April 2017
Number of Pages: 95
Institution: Università degli Studi di Napoli Federico II
Department: Scienze Mediche Traslazionali
Dottorato: Medicina clinica e sperimentale
Ciclo di dottorato: 29
Coordinatore del Corso di dottorato:
nomeemail
Marone, Giannimarone@unina.it
Tutor:
nomeemail
Beguinot, FrancescoUNSPECIFIED
Date: 10 April 2017
Number of Pages: 95
Uncontrolled Keywords: Methylglyoxal, endothelium
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/05 - Patologia clinica
Date Deposited: 02 May 2017 08:25
Last Modified: 13 Mar 2018 10:33
URI: http://www.fedoa.unina.it/id/eprint/11755
DOI: 10.6093/UNINA/FEDOA/11755

Abstract

Much of the morbidity and mortality associated with diabetes mellitus (DM) reflects its deleterious effect on micro- and macro-circulation. DM impairs physiological angiogenesis, leading to long-term complications, by molecular mechanisms that are not fully understood. The generation of Advanced Glycation End-products (AGEs) has an important role in the development of hyperglycemia-induced endothelial damage. Moreover, previous evidence demonstrated that exposure of endothelial cells to hyperglycemia induces sustained activation of the transcription factor nuclear-κB (NF-κB), at least in part by the AGEs/RAGE pathways, leading to accelerated vascular disease. One of the main precursors of AGEs in endothelial cells is Methylglyoxal (MGO), a highly reactive dycarbonyl detoxified by the Glyoxalase System, of which Glyoxalase 1 (Glo1) is the rate limiting enzyme. In this study, we aim at evaluating the effect of MGO on the angiogenic ability of aortic endothelial cells isolated from Glo1 knock-down mice (Glo1KD MAECs) and their WT littermates (WT MAECs). Glo1KD MAECs show a reduced expression of Glo1 that is paralleled to an increase of MGO accumulation. This leads to an impairment of angiogenic ability of Glo1KD MAECs characterized by a reduced proliferation, migration and invasion. Both protein and mRNA levels of the antiangiogenic HoxA5 gene are increased in Glo1KD MAECs compared to WT MAECs. Interestingly, HoxA5 silencing, is able to improve migration and invasion of Glo1KD MAECs. Moreover, MGO accumulation in Glo1KD MAECs causes the overexpression of NF-κB-p65 that is also associated to a higher cytoplasmic and nuclear protein levels. Interestingly, there is an increased binding of NF-κB-p65 to HoxA5 promoter in Glo1KD MAECs compared to WT MAECs, and NF-κB inhibition results in the reduction of HoxA5 expression. This study demonstrates that, through NF-κB-p65 activation, high levels of MGO impair angiogenic ability of MAECs via a mechanism involving the antiangiogenic factor HoxA5. Further investigations will allow to identify new strategies for the prevention and treatment of microvascular complications associated to diabetes.

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