Selective Rac-1 inhibition protects from diabetes-induced vascular injury.
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.
Vecchione
Carmine
C
Department of AngioCardioNeurology, IRCCS NEUROMED, Località Camerelle, 86077 Pozzilli, Italy.
Aretini
Alessandra
A
Marino
Gennaro
G
Bettarini
Umberto
U
Poulet
Roberta
R
Maffei
Angelo
A
Sbroggiò
Mauro
M
Pastore
Lucio
L
Gentile
Maria Teresa
MT
Notte
Antonella
A
Iorio
Luca
L
Hirsch
Emilio
E
Tarone
Guido
G
Lembo
Giuseppe
G
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
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