AKT participates in endothelial dysfunction in hypertension

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.