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AKT participates in endothelial dysfunction in hypertension

Guido Iaccarino1, Michele Ciccarelli, Daniela Sorriento

  • 1Department of Clinical Medicine, University of Naples Federico II, Italy. guiaccar@unina.it

Circulation
|May 12, 2004
PubMed

Insights

In hypertension, impaired AKT kinase localization contributes to endothelial dysfunction. Restoring AKT1 gene expression in spontaneously hypertensive rats normalized blood vessel function, suggesting a therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Hypertension Research

Background:

  • Hypertension is associated with reduced nitric oxide production and impaired endothelial vasodilation.
  • The AKT kinase phosphorylates and activates endothelial nitric oxide synthase; its dysfunction may underlie endothelial dysfunction.

Purpose of the Study:

  • To investigate the physiological role of AKT kinase in endothelial function in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR).
  • To determine if AKT1 gene transfer can ameliorate endothelial dysfunction in spontaneously hypertensive rats.

Main Methods:

  • Adenoviral vectors were used to deliver the human AKT1 gene to the carotid artery endothelium in WKY and SHR.
  • In vitro endothelial-dependent vasorelaxation responses to acetylcholine, isoproterenol, and insulin were assessed.
  • In vivo carotid blood flow was measured using Doppler ultrasound.
  • AKT phosphorylation, activity, and cellular localization were examined in cultured endothelial cells.

Main Results:

  • Endothelial vasorelaxations were blunted in SHR compared to WKY rats, and AKT1 gene transfer normalized these responses.
  • In vivo carotid blood flow was reduced in SHR and restored to WKY levels after AKT1 gene transfer.
  • Endothelial cells from SHR exhibited mislocalization of the AKT kinase compared to WKY rats.

Conclusions:

  • Impaired membrane localization of AKT contributes to endothelial dysfunction in spontaneously hypertensive rats.
  • AKT plays a significant role in the pathophysiology of endothelial dysfunction associated with hypertension.
Abstract

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