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(Circulation Research. 2006;98:218.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Selective Rac-1 Inhibition Protects From Diabetes-Induced Vascular Injury

Carmine Vecchione, Alessandra Aretini, Gennaro Marino, Umberto Bettarini, Roberta Poulet, Angelo Maffei, Mauro Sbroggiò, Lucio Pastore, Maria Teresa Gentile, Antonella Notte, Luca Iorio, Emilio Hirsch, Guido Tarone, Giuseppe Lembo

From the Department of Angio-Cardio-Neurology, IRCCS "NEUROMED" (C.V., A.A., G.M., U.B., R.P., A.M., M.T.G., A.N., L.I., G.L.), Pozzilli (IS); the Department of Genetics, Biology, and Biochemistry (M.S., E.H., G.T.), University of Turin; Biochemistry and Medical Biotechnology (L.P.), University of Naples; and the Department of Experimental Medicine and Pathology (G.L.), "La Sapienza" University of Rome, Italy.

Correspondence to Giuseppe Lembo, MD, PhD, Department of AngioCardioNeurology, IRCCS Neuromed, Località Camerelle, 86077 POZZILLI (IS), Italy. E-mail lembo{at}neuromed.it

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.

Key Words: Rac-1 • free radicals • diabetes mellitus • vessels

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