TY - JOUR
T1 - AKT participates in endothelial dysfunction in hypertension
AU - Iaccarino, Guido
AU - Ciccarelli, Michele
AU - Sorriento, Daniela
AU - Cipolletta, Ersilia
AU - Cerullo, Vincenzo
AU - Iovino, Gianni Luigi
AU - Paudice, Alessandro
AU - Elia, Andrea
AU - Santulli, Gaetano
AU - Campanile, Alfonso
AU - Arcucci, Oreste
AU - Pastore, Lucio
AU - Salvatore, Francesco
AU - Condorelli, Gianluigi
AU - Trimarco, Bruno
PY - 2004/6/1
Y1 - 2004/6/1
N2 - 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 AKTI 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.
AB - 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 AKTI 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.
KW - Endothelium
KW - Gene therapy
KW - Hypertension
KW - Signal transduction
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U2 - 10.1161/01.CIR.0000129768.35536.FA
DO - 10.1161/01.CIR.0000129768.35536.FA
M3 - Article
C2 - 15136501
AN - SCOPUS:2642574211
SN - 0009-7322
VL - 109
SP - 2587
EP - 2593
JO - Circulation
JF - Circulation
IS - 21
ER -