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

Circulation research | May 8, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19342603

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.

Pubmed ID: 19342603 RIS Download

Mesh terms: Animals | Blood Pressure | Cells, Cultured | Dietary Fats | Disease Models, Animal | Dose-Response Relationship, Drug | Endothelial Cells | Endothelium, Vascular | Enzyme Inhibitors | Fatty Acids, Nonesterified | Glucose Intolerance | Hypertension | Insulin | Insulin Resistance | Mice | Mice, Inbred C57BL | Mice, Knockout | Mitogen-Activated Protein Kinase 1 | Mitogen-Activated Protein Kinase 3 | Nitric Oxide | Nitric Oxide Synthase Type III | Obesity | Palmitic Acid | Phosphorylation | Proto-Oncogene Proteins c-akt | Receptor, Insulin | Signal Transduction | Time Factors | Vasoconstriction | Vasoconstrictor Agents | Vasodilation | Vasodilator Agents

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK056886
  • Agency: NIDDK NIH HHS, Id: R01 DK081842
  • Agency: NIDDK NIH HHS, Id: R01 DK092065
  • Agency: NHLBI NIH HHS, Id: R01 HL 070070
  • Agency: NHLBI NIH HHS, Id: R01 HL070070
  • Agency: NHLBI NIH HHS, Id: R01 HL070070-04
  • Agency: NHLBI NIH HHS, Id: R15 HL 091493-01
  • Agency: NHLBI NIH HHS, Id: U01 HL087947
  • Agency: NHLBI NIH HHS, Id: U01 HL087947-04

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