title: SRT1720 counteracts glucosamine-induced endoplasmic reticulum stress and endothelial dysfunction.
abstract: OBJECTIVE
  We hypothesized that a disproportionate activation of the glucosamine (GlcN) pathway, caused by a prolonged exposure to hyperglycaemia, could impair endothelial integrity promoting endoplasmic reticulum (ER) stress. We also tested the possibility that SRT1720 may be able to counteract GlcN-induced ER stress.
  
  
  RESULTS
  Human umbilical vein endothelial cells (HUVECs), human cardiac microvascular endothelial cells, and human retinal endothelial cells were treated with GlcN in the presence or absence of the chemical chaperone phenyl butyric acid (PBA) or SRT1720. Expression of ER stress markers, activation of apoptosis, and pro-inflammatory/pro-thrombotic pathways were evaluated by western blot, real-time RT-PCR, and ELISA assays. GlcN treatment resulted in a significantly increased expression of the major ER stress mediators. ER stress activation was paralleled by increased levels of apoptotic markers and by pro-inflammatory/pro-coagulant pathway activation. In HUVECs, ER stress inhibition by PBA alleviated a GlcN-induced pro-apoptotic and pro-inflammatory/pro-thrombotic state, suggesting a crucial role of ER stress in endothelial dysfunction caused by GlcN. Furthermore, SRT1720 treatment abolished GlcN-induced ER stress and reversed its effects on apoptosis and pro-inflammatory/pro-coagulant pathways. This SRT1720 action was mediated by its ability to modulate Raptor acetylation, thus inhibiting mammalian target of Rapamycin complex 1 (mTORC1)-dependent protein synthesis and alleviating ER overload.
  
  
  CONCLUSIONS
  Our data show that GlcN promotes a pro-apoptotic and pro-inflammatory/pro-thrombotic phenotype in endothelial cells by activating ER stress. The observation that SRT1720, inhibiting ER stress, was able to counteract GlcN effects lays the basis for future studies aimed to exploit this drug and cognate compounds in the treatment of endothelial dysfunction and atherosclerosis.
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Teresa Vanessa
authors.initials: TV
authors.lastname: Fiorentino
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Procopio
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Elettra
authors.initials: E
authors.lastname: Mancuso
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Gaetano Paride
authors.initials: GP
authors.lastname: Arcidiacono
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Arturi
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Sciacqua
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perticone
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy hribal@unicz.it.
authors.forename: Marta Letizia
authors.initials: ML
authors.lastname: Hribal
authors.affiliation: Department of Medical and Surgical Sciences, University Magna Græcia of Catanzaro, Viale Europa, Catanzaro 88100, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005944:Glucosamine / Q000494:pharmacology*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; C525422:SRT1720; D005944:Glucosamine
keywords: Endoplasmic reticulum stress; Endothelial dysfunction; Hexosamine pathway; SRT1720; mTOR signalling