title: Unacylated ghrelin induces oxidative stress resistance in a glucose intolerance and peripheral artery disease mouse model by restoring endothelial cell miR-126 expression.
abstract: Reactive oxygen species (ROS) are crucial in long-term diabetes complications, including peripheral artery disease (PAD). In this study, we have investigated the potential clinical impact of unacylated ghrelin (UnAG) in a glucose intolerance and PAD mouse model. We demonstrate that UnAG is able to protect skeletal muscle and endothelial cells (ECs) from ROS imbalance in hind limb ischemia-subjected ob/ob mice. This effect translates into reductions in hind limb functional impairment. We show that UnAG rescues sirtuin 1 (SIRT1) activity and superoxide dismutase-2 (SOD-2) expression in ECs. This leads to SIRT1-mediated p53 and histone 3 lysate 56 deacetylation and results in reduced EC senescence in vivo. We demonstrate, using small interfering RNA technology, that SIRT1 is also crucial for SOD-2 expression. UnAG also renews micro-RNA (miR)-126 expression, resulting in the posttranscriptional regulation of vascular cell adhesion molecule 1 expression and a reduced number of infiltrating inflammatory cells in vivo. Loss-of-function experiments that target miR-126 demonstrate that miR-126 also controls SIRT1 and SOD-2 expression, thus confirming its role in driving UnAG-mediated EC protection against ROS imbalance. These results indicate that UnAG protects vessels from ROS imbalance in ob/ob mice by rescuing miR-126 expression, thus emphasizing its potential clinical impact in avoiding limb loss in PAD.
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Togliatto
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Trombetta
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dentelli
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gallo
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Rosso
authors.affiliation: Department of Anesthesiology and Intensive Care, University of Turin, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cotogni
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Riccarda
authors.initials: R
authors.lastname: Granata
authors.affiliation: Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy falcioni@ifo.it.
authors.forename: Rita
authors.initials: R
authors.lastname: Falcioni
authors.affiliation: Alizé Pharma, Ecully, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Delale
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Ghigo
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy mariafelice.brizzi@unito.it.
authors.forename: Maria Felice
authors.initials: MF
authors.lastname: Brizzi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D054439:Ghrelin / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D058729:Peripheral Arterial Disease / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D054439:Ghrelin; D035683:MicroRNAs; D056564:Sirtuin 1; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C545201:MIRN126 microRNA, mouse