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(Circulation. 2004;109:2587-2593.)
© 2004 American Heart Association, Inc.

Basic Science Reports

AKT Participates in Endothelial Dysfunction in Hypertension

Guido Iaccarino, MD, PhD; Michele Ciccarelli, MD; Daniela Sorriento, BS; Ersilia Cipolletta, MD; Vincenzo Cerullo, BS; Gianni Luigi Iovino, MD; Alessandro Paudice, MD; Andrea Elia, MD; Gaetano Santulli, MS; Alfonso Campanile, MS; Oreste Arcucci, MD; Lucio Pastore, MD, PhD; Francesco Salvatore, MD, PhD; Gianluigi Condorelli, MD, PhD; Bruno Trimarco, MD

From the Departments of Clinical Medicine, Cardiovascular and Immunological Sciences (G.I., M.C., D.S., E.C., G.L.I., A.P., A.E., G.S., A.C., O.A., B.T.), and Biochemistry and Medical Biotechnology (V.C., L.P., F.S.), and School of Biotechnologican Sciences (L.P., F.S.), University of Naples Federico II, Italy; CEINGE-Biotecnologie Avanzate, Naples (L.P., F.S.); and San Raffaele Biomedical Science Park of Rome (G.C.), Italy.

Correspondence to Guido Iaccarino, MD, PhD, Medicina Clinica, Scienze Cardiovascolari ed Immunologiche, Federico II University, Via Pansini 5, Edificio 2, 80131 Naples, Italy. E-mail guiaccar{at}unina.it

Received August 11, 2003; de novo received December 12, 2003; accepted February 11, 2004.

Background— In hypertension, reduced nitric oxide production and blunted endothelial vasorelaxation are observed. It was recently reported that AKT phosphorylates and activates endothelial nitric oxide synthase and that impaired kinase activity may be involved in endothelial dysfunction.

Methods and Results— To identify the physiological role of the kinase in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), we used adenoviral vectors to transfer the human AKT1 gene selectively to the common carotid endothelium. In vitro, endothelial vasorelaxations to acetylcholine, isoproterenol, and insulin were blunted in control carotids from SHR compared with WKY rats, and human AKT1 overexpression corrected these responses. Similarly, blood flow assessed in vivo by Doppler ultrasound was reduced in SHR compared with WKY carotids and normalized after AKT1 gene transfer. In primary cultured endothelial cells, we evaluated AKT phosphorylation, activity, and compartmentalization and observed a mislocalization of the kinase in SHR.

Conclusions— We conclude that AKT participates in the settings of endothelial dysfunction in SHR rats by impaired membrane localization. Our data suggest that AKT is involved in endothelium dysfunction in hypertension.

Key Words: endothelium • gene therapy • hypertension • signal transduction

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