Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop
Hema ViswambharanFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Nadira YuldashevaFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Anshuman SenguptaFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Helen ImrieFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Matthew GageFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Natalie J HaywoodFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Andrew MN WalkerFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Anna SkromnaFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Natallia MakovaFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Stacey GallowayFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Pooja ShahFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Piruthivi SukumarFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Karen E. PorterFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Peter J. GrantFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Ajay M. ShahFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Célio X.C. SantosFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Jing LiFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)David J. BeechFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Stephen B. WheatcroftFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Richard M. CubbonFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)Mark T. KearneyFrom the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (H.V., N.Y.Y., A.S., H.I., N.H., A.M.N.W., A.S., N.M., S.G., P. Shah, P. Sukumar, K.E.P., P.J.G., J.L., D.J.B., S.B.W., R.M.C., M.T.K.); Division of Medicine, Department of Metabolism & Experimental Therapeutics, University College London, United Kingdom (M.C.G.); and British Heart Foundation Centre of Research Excellence, King’s College London, United Kingdom (A.M.S., C.X.C.S.)
2016en
ABI
Аннотация
RATIONALE: In the endothelium, insulin stimulates endothelial NO synthase (eNOS) to generate the antiatherosclerotic signaling radical NO. Insulin-resistant type 2 diabetes mellitus is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. OBJECTIVE: To answer this question, we generated a mouse with endothelial cell (EC)-specific overexpression of the human insulin receptor (hIRECO) using the Tie2 promoter-enhancer. METHODS AND RESULTS: hIRECO demonstrated significant endothelial dysfunction measured by blunted endothelium-dependent vasorelaxation to acetylcholine, which was normalized by a specific Nox2 NADPH oxidase inhibitor. Insulin-stimulated phosphorylation of protein kinase B was increased in hIRECO EC as was Nox2 NADPH oxidase-dependent generation of superoxide, whereas insulin-stimulated and shear stress-stimulated eNOS activations were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of proline-rich tyrosine kinase 2 that phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of proline-rich tyrosine kinase 2 improved insulin-induced and shear stress-induced eNOS activation in hIRECO EC. CONCLUSIONS: Enhancing insulin sensitivity specifically in EC leads to a paradoxical decline in endothelial function, mediated by increased tyrosine phosphorylation of eNOS and excess Nox2-derived superoxide. Increased EC insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide. Inhibition of proline-rich tyrosine kinase 2 restores insulin-induced and shear stress-induced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide.
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