(Circulation. 2000;101:1539.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Roles for Insulin Receptor, PI3-Kinase, and Akt in Insulin-Signaling Pathways Related to Production of Nitric Oxide in Human Vascular Endothelial Cells
From the Hypertension-Endocrine Branch (G.Z., F.H.N., L.V.R., L.-N.C., M.J.Q.) and Hematology Branch (M.K.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; and the Center for Biological Experimental Research (H.M.), Food and Drug Administration, Bethesda, Md.
Correspondence to Michael J. Quon, MD, PhD, Hypertension-Endocrine Branch, NHLBI, NIH, Bldg 10, Room 8C-218, 10 Center Dr MSC 1755, Bethesda, MD 20892-1755. E-mail quonm{at}nih.gov
Background—Previously, we demonstrated that insulin stimulates production of nitric oxide (NO) in endothelial cells. However, specific insulin-signaling pathways mediating production of NO have not been elucidated.
Methods and Results—We developed methods for transfection of
human umbilical vein endothelial cells (HUVECs) and
direct measurement of NO to begin defining insulin-signaling pathways
related to NO production. HUVECs were cotransfected with
enhanced Green Fluorescent Protein (eGFP) and
another gene of interest. Transfection efficiencies >95% were
obtained by selecting cells expressing eGFP.
Overexpression of insulin receptors in HUVECs resulted in an 
3-fold
increase in production of NO in response to insulin. In
contrast, HUVECs overexpressing a tyrosine kinase–deficient mutant
insulin receptor had a dose-response curve similar to that of control
cells. Overexpression of inhibitory mutants of either
phosphatidylinositol 3-kinase (PI3K) or Akt resulted in
nearly complete inhibition of insulin-stimulated production of
NO. Overexpression of an inhibitory mutant of
Ras had a much smaller effect.
Conclusions—Receptor kinase activity is necessary to mediate production of NO through the insulin receptor. Both PI3K and Akt contribute importantly to this process, whereas the contribution of Ras is small.
Key Words: insulin • endothelium • signal transduction • nitric oxide • receptors
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F. Kim, K. A. Tysseling, J. Rice, M. Pham, L. Haji, B. M. Gallis, A. S. Baas, P. Paramsothy, C. M. Giachelli, M. A. Corson, et al. Free Fatty Acid Impairment of Nitric Oxide Production in Endothelial Cells Is Mediated by IKK{beta} Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 989 - 994. [Abstract] [Full Text] [PDF]
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K. Sydow, C. E Mondon, and J. P Cooke Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA Vascular Medicine, May 1, 2005; 10(2_suppl): S35 - S43. [Abstract] [PDF]
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M. O. Goodarzi, K. D. Taylor, X. Guo, M. J. Quinones, J. Cui, X. Li, T. Hang, H. Yang, E. Holmes, W. A. Hsueh, et al. Variation in the Gene for Muscle-Specific AMP Deaminase Is Associated With Insulin Clearance, a Highly Heritable Trait Diabetes, April 1, 2005; 54(4): 1222 - 1227. [Abstract] [Full Text] [PDF]
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R. Rossi, E. Cioni, A. Nuzzo, G. Origliani, and M. G. Modena Endothelial-Dependent Vasodilation and Incidence of Type 2 Diabetes in a Population of Healthy Postmenopausal Women Diabetes Care, March 1, 2005; 28(3): 702 - 707. [Abstract] [Full Text] [PDF]
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C. Rask-Madsen and G. L. King Proatherosclerotic Mechanisms Involving Protein Kinase C in Diabetes and Insulin Resistance Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 487 - 496. [Abstract] [Full Text] [PDF]
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T. Kobayashi, K. Taguchi, T. Yasuhiro, T. Matsumoto, and K. Kamata Impairment of PI3-K/Akt Pathway Underlies Attenuated Endothelial Function in Aorta of Type 2 Diabetic Mouse Model Hypertension, December 1, 2004; 44(6): 956 - 962. [Abstract] [Full Text] [PDF]
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C. C. L. Wang, M. L. Goalstone, and B. Draznin Molecular Mechanisms of Insulin Resistance That Impact Cardiovascular Biology Diabetes, November 1, 2004; 53(11): 2735 - 2740. [Abstract] [Full Text] [PDF]
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T. Nystrom, A. Nygren, and A. Sjoholm Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E919 - E925. [Abstract] [Full Text] [PDF]
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E. C. Eringa, C. D. A. Stehouwer, G. P. van Nieuw Amerongen, L. Ouwehand, N. Westerhof, and P. Sipkema Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2043 - H2048. [Abstract] [Full Text] [PDF]
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H.-N. Huang, P.-J. Lu, W.-C. Lo, C.-H. Lin, M. Hsiao, and C.-J. Tseng In Situ Akt Phosphorylation in the Nucleus Tractus Solitarii Is Involved in Central Control of Blood Pressure and Heart Rate Circulation, October 19, 2004; 110(16): 2476 - 2483. [Abstract] [Full Text] [PDF]
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S. B. Wheatcroft, A. M. Shah, J.-M. Li, E. Duncan, B. T. Noronha, P. A. Crossey, and M. T. Kearney Preserved Glucoregulation but Attenuation of the Vascular Actions of Insulin in Mice Heterozygous for Knockout of the Insulin Receptor Diabetes, October 1, 2004; 53(10): 2645 - 2652. [Abstract] [Full Text] [PDF]
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D. Fulton, R. Babbitt, S. Zoellner, J. Fontana, L. Acevedo, T. J. McCabe, Y. Iwakiri, and W. C. Sessa Targeting of Endothelial Nitric-oxide Synthase to the Cytoplasmic Face of the Golgi Complex or Plasma Membrane Regulates Akt- Versus Calcium-dependent Mechanisms for Nitric Oxide Release J. Biol. Chem., July 16, 2004; 279(29): 30349 - 30357. [Abstract] [Full Text] [PDF]
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F. Perticone, A. Sciacqua, A. Scozzafava, G. Ventura, E. Laratta, A. Pujia, M. Federici, R. Lauro, and G. Sesti Impaired Endothelial Function in Never-Treated Hypertensive Subjects Carrying the Arg972 Polymorphism in the Insulin Receptor Substrate-1 Gene J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3606 - 3609. [Abstract] [Full Text] [PDF]
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T. Kobayashi, T. Matsumoto, K. Ooishi, and K. Kamata Differential expression of {alpha}2D-adrenoceptor and eNOS in aortas from early and later stages of diabetes in Goto-Kakizaki rats Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H135 - H148. [Abstract] [Full Text] [PDF]
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A. Natali, S. Baldeweg, E. Toschi, B. Capaldo, D. Barbaro, A. Gastaldelli, J. S. Yudkin, and E. Ferrannini Vascular Effects of Improving Metabolic Control With Metformin or Rosiglitazone in Type 2 Diabetes Diabetes Care, June 1, 2004; 27(6): 1349 - 1357. [Abstract] [Full Text] [PDF]
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M. A. Vincent, L. H. Clerk, J. R. Lindner, A. L. Klibanov, M. G. Clark, S. Rattigan, and E. J. Barrett Microvascular Recruitment Is an Early Insulin Effect That Regulates Skeletal Muscle Glucose Uptake In Vivo Diabetes, June 1, 2004; 53(6): 1418 - 1423. [Abstract] [Full Text] [PDF]
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S. I. Chisalita and H. J. Arnqvist Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E896 - E901. [Abstract] [Full Text] [PDF]
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F. Andreozzi, E. Laratta, A. Sciacqua, F. Perticone, and G. Sesti Angiotensin II Impairs the Insulin Signaling Pathway Promoting Production of Nitric Oxide by Inducing Phosphorylation of Insulin Receptor Substrate-1 on Ser312 and Ser616 in Human Umbilical Vein Endothelial Cells Circ. Res., May 14, 2004; 94(9): 1211 - 1218. [Abstract] [Full Text] [PDF]
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J. R. Sowers Insulin resistance and hypertension Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1597 - H1602. [Abstract] [Full Text] [PDF]
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V. Fonseca, C. Desouza, S. Asnani, and I. Jialal Nontraditional Risk Factors for Cardiovascular Disease in Diabetes Endocr. Rev., February 1, 2004; 25(1): 153 - 175. [Abstract] [Full Text] [PDF]
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F. Pistrosch, J. Passauer, S. Fischer, K. Fuecker, M. Hanefeld, and P. Gross In Type 2 Diabetes, Rosiglitazone Therapy for Insulin Resistance Ameliorates Endothelial Dysfunction Independent of Glucose Control Diabetes Care, February 1, 2004; 27(2): 484 - 490. [Abstract] [Full Text] [PDF]
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L. Zhang, M. A. Vincent, S. M. Richards, L. H. Clerk, S. Rattigan, M. G. Clark, and E. J. Barrett Insulin Sensitivity of Muscle Capillary Recruitment In Vivo Diabetes, February 1, 2004; 53(2): 447 - 453. [Abstract] [Full Text]
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S. Vehkavaara and H. Yki-Jarvinen 3.5 Years of Insulin Therapy With Insulin Glargine Improves In Vivo Endothelial Function in Type 2 Diabetes Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 325 - 330. [Abstract] [Full Text]
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M. Federici, A. Pandolfi, E. A. De Filippis, G. Pellegrini, R. Menghini, D. Lauro, M. Cardellini, M. Romano, G. Sesti, R. Lauro, et al. G972R IRS-1 Variant Impairs Insulin Regulation of Endothelial Nitric Oxide Synthase in Cultured Human Endothelial Cells Circulation, January 27, 2004; 109(3): 399 - 405. [Abstract] [Full Text] [PDF]
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U. Campia, G. Sullivan, M. B. Bryant, M. A. Waclawiw, M. J. Quon, and J. A. Panza Insulin impairs endothelium-dependent vasodilation independent of insulin sensitivity or lipid profile Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H76 - H82. [Abstract] [Full Text] [PDF]
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L. Bergandi, F. Silvagno, I. Russo, C. Riganti, G. Anfossi, E. Aldieri, D. Ghigo, M. Trovati, and A. Bosia Insulin Stimulates Glucose Transport Via Nitric Oxide/Cyclic GMP Pathway in Human Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2215 - 2221. [Abstract] [Full Text] [PDF]
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