AKT participates in endothelial dysfunction in hypertension.
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.


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.
Iaccarino
Guido
G
Department of Clinical Medicine, University of Naples Federico II, Italy. guiaccar@unina.it
Ciccarelli
Michele
M
Sorriento
Daniela
D
Cipolletta
Ersilia
E
Cerullo
Vincenzo
V
Iovino
Gianni Luigi
GL
Paudice
Alessandro
A
Elia
Andrea
A
Santulli
Gaetano
G
Campanile
Alfonso
A
Arcucci
Oreste
O
Pastore
Lucio
L
Salvatore
Francesco
F
Condorelli
Gianluigi
G
Trimarco
Bruno
B
D000109:Acetylcholine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D002462:Cell Membrane / Q000201:enzymology; D002478:Cells, Cultured / Q000201:enzymology; D042783:Endothelial Cells / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D007269:Injections, Intra-Arterial; D007328:Insulin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D007328:Insulin; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D014665:Vasodilator Agents; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D007545:Isoproterenol; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester