Contribution of insulin and Akt1 signaling to endothelial nitric oxide synthase in the regulation of endothelial function and blood pressure.

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 phosphorylation.

• Authors: J David Symons, Shawna L McMillin, Christian Riehle, Jason Tanner, Milda Palionyte, Elaine Hillas, Deborah Jones, Robert C Cooksey, Morris J Birnbaum, Donald A McClain, Quan-Jiang Zhang, Derrick Gale, Lloyd J Wilson, E Dale Abel
• Journal: Circulation research (Circ Res) Vol. 104 Issue 9 Pg. 1085-94 (May 08 2009) ISSN: 1524-4571 [Electronic] United States
• PMID: 19342603 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Enzyme Inhibitors
• Fatty Acids, Nonesterified
• Insulin
• Vasoconstrictor Agents
• Vasodilator Agents
• Palmitic Acid
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Receptor, Insulin
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Blood Pressure
• Cells, Cultured
• Dietary Fats
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endothelial Cells (enzymology)
• Endothelium, Vascular (drug effects, enzymology, physiopathology)
• Enzyme Inhibitors (pharmacology)
• Fatty Acids, Nonesterified (metabolism)
• Glucose Intolerance (enzymology, physiopathology)
• Hypertension (enzymology, etiology, physiopathology)
• Insulin (metabolism)
• Insulin Resistance
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, metabolism)
• Obesity (enzymology, physiopathology)
• Palmitic Acid (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (deficiency, genetics, metabolism)
• Receptor, Insulin (deficiency, genetics, metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Vasoconstriction
• Vasoconstrictor Agents (pharmacology)
• Vasodilation
• Vasodilator Agents (pharmacology)