Journal article
Contribution of Insulin and Akt1 Signaling to Endothelial Nitric Oxide Synthase in the Regulation of Endothelial Function and Blood Pressure
Circulation research, Vol.104(9), pp.1085-1094
05/08/2009
DOI: 10.1161/CIRCRESAHA.108.189316
PMCID: PMC2936913
PMID: 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 phosphorylation.
Details
- Title: Subtitle
- Contribution of Insulin and Akt1 Signaling to Endothelial Nitric Oxide Synthase in the Regulation of Endothelial Function and Blood Pressure
- Creators
- J. David Symons - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineShawna L McMillin - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineChristian Riehle - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineJason Tanner - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineMilda Palionyte - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineElaine Hillas - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineDeborah Jones - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineRobert C Cooksey - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineMorris J Birnbaum - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineDonald A McClain - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineQuan-Jiang Zhang - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineDerrick Gale - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineLloyd J Wilson - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of MedicineE. Dale Abel - From the College of Health (J.D.S., S.L.M., J.T., M.P., Q.-J.Z., D.G., L.J.W.), University of Utah, Salt Lake City; Division of Endocrinology, Metabolism and Diabetes (J.D.S., S.L.M., C.R., J.T., M.P., D.J., R.C.C., D.A.M., Q.-J.Z., D.G., L.J.W., E.D.A.), Program in Molecular Medicine (C.R., E.D.A.), and Department of Human Genetics (E.H.), University of Utah School of Medicine, Salt Lake City; and Institute for Diabetes, Obesity and Metabolism (M.J.B.), University of Pennsylvania School of Medicine
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.104(9), pp.1085-1094
- DOI
- 10.1161/CIRCRESAHA.108.189316
- PMID
- 19342603
- PMCID
- PMC2936913
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 05/08/2009
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024545902771
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