title: Selective Rac-1 inhibition protects from diabetes-induced vascular injury.
abstract: Diabetes mellitus is a main risk factor for vascular diseases. Vascular injury induced by diabetes mellitus is characterized by endothelial dysfunction attributable to an increased oxidative stress. So far, the molecular mechanisms involved in the vasculotoxic effects of diabetes are only partially known. We examined the effect of diabetes mellitus on oxidative stress and Rac-1 activation, a small G-protein involved in the activation of NADPH oxidase. Our results show that oxidative stress in vessels of different murine models of diabetes mellitus and in endothelial cells treated with high glucose is associated with an increased Rac-1/PAK binding and Rac-1 translocation from cytosol to plasma membrane, thus demonstrating an enhanced Rac-1 activity. More important, selective Rac-1 inhibition by an adenoviral vector carrying a dominant negative mutant of Rac-1 protected from oxidative stress and vascular dysfunction induced by diabetes mellitus. Our study demonstrates that Rac-1 plays a crucial role in diabetes-induced vascular injury, and it could be a target of novel therapeutic approaches to reduce vascular risk in diabetes mellitus.
authors.affiliation: Department of AngioCardioNeurology, IRCCS NEUROMED, Località Camerelle, 86077 Pozzilli, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.forename: Alessandra
authors.initials: A
authors.lastname: Aretini
authors.forename: Gennaro
authors.initials: G
authors.lastname: Marino
authors.forename: Umberto
authors.initials: U
authors.lastname: Bettarini
authors.forename: Roberta
authors.initials: R
authors.lastname: Poulet
authors.forename: Angelo
authors.initials: A
authors.lastname: Maffei
authors.forename: Mauro
authors.initials: M
authors.lastname: Sbroggiò
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Gentile
authors.forename: Antonella
authors.initials: A
authors.lastname: Notte
authors.forename: Luca
authors.initials: L
authors.lastname: Iorio
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000502:physiology; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000502:physiology; D064546:Protein Kinase C beta; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D009479:Neuropeptides; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D019255:NADPH Oxidases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D005947:Glucose