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.
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 hypertensiverats (SHR), we used adenoviral vectors to transfer the humanAKT1 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 humanAKT1 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.
Authors: M Ciccarelli; G Santulli; A Campanile; G Galasso; P Cervèro; G G Altobelli; V Cimini; L Pastore; F Piscione; B Trimarco; G Iaccarino Journal: Br J Pharmacol Date: 2007-12-17 Impact factor: 8.739
Authors: Qi Yuan; Jingyi Yang; Gaetano Santulli; Steven R Reiken; Anetta Wronska; Mindy M Kim; Brent W Osborne; Alain Lacampagne; Yuxin Yin; Andrew R Marks Journal: Proc Natl Acad Sci U S A Date: 2016-07-08 Impact factor: 11.205
Authors: Zachary I Grunewald; Francisco I Ramirez-Perez; Makenzie L Woodford; Mariana Morales-Quinones; Salvador Mejia; Camila Manrique-Acevedo; Ulrich Siebenlist; Luis A Martinez-Lemus; Bysani Chandrasekar; Jaume Padilla Journal: Hypertension Date: 2020-08-24 Impact factor: 10.190
Authors: A Cittadini; M G Monti; G Iaccarino; F Di Rella; P N Tsichlis; A Di Gianni; H Strömer; D Sorriento; C Peschle; B Trimarco; L Saccà; G Condorelli Journal: Gene Ther Date: 2006-01 Impact factor: 5.250