Published Online
on May 10, 2004

A more recent version of this article appeared on June 1, 2004

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Submitted on August 11, 2003
Revised on December 12, 2003
Accepted on February 11, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: guiaccar{at}unina.it.

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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