Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase
in the regulation of endothelial function and blood pressure.
Authors Symons JD, McMillin SL, Riehle C, Tanner J, Palionyte M, Hillas E, Jones D,
Cooksey RC, Birnbaum MJ, McClain DA, Zhang QJ, Gale D, Wilson LJ, Abel ED
Submitted By E. Dale Abel on 4/26/2010
Status Published
Journal Circulation research
Year 2009
Date Published 5/8/2009
Volume : Pages 104 : 1085 - 1094
PubMed Reference 19342603
Abstract Impaired insulin signaling via phosphatidylinositol 3-kinase/Akt to endothelial
nitric oxide synthase (eNOS) in the vasculature has been postulated to lead to
arterial dysfunction and hypertension in obesity and other insulin resistant
states. To investigate this, we compared insulin signaling in the vasculature,
endothelial function, and systemic blood pressure in mice fed a high-fat (HF)
diet to mice with genetic ablation of insulin receptors in all vascular tissues
(TTr-IR(-/-)) or mice with genetic ablation of Akt1 (Akt1-/-). HF mice developed
obesity, impaired glucose tolerance, and elevated free fatty acids that was
associated with endothelial dysfunction and hypertension. Basal and
insulin-mediated phosphorylation of extracellular signal-regulated kinase 1/2
and Akt in the vasculature was preserved, but basal and insulin-stimulated eNOS
phosphorylation was abolished in vessels from HF versus lean mice. In contrast,
basal vascular eNOS phosphorylation, endothelial function, and blood pressure
were normal despite absent insulin-mediated eNOS phosphorylation in TTr-IR(-/-)
mice and absent insulin-mediated eNOS phosphorylation via Akt1 in Akt1-/- mice.
In cultured endothelial cells, 6 hours of incubation with palmitate attenuated
basal and insulin-stimulated eNOS phosphorylation and NO production despite
normal activation of extracellular signal-regulated kinase 1/2 and Akt.
Moreover, incubation of isolated arteries with palmitate impaired
endothelium-dependent but not vascular smooth muscle function. Collectively,
these results indicate that lower arterial eNOS phosphorylation, hypertension,
and vascular dysfunction following HF feeding do not result from defective
upstream signaling via Akt, but from free fatty acid-mediated impairment of eNOS

Investigators with authorship
E. Dale AbelUniversity of Iowa


Akt1thymoma viral proto-oncogene 1
Nos3nitric oxide synthase 3, endothelial cell