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Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signalling Loop

Viswambharan, H; Yuldasheva, NY; Sengupta, A; Imrie, H; Gage, MC; Haywood, NJ; Walker, AM; ... Kearney, MT; + view all (2017) Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signalling Loop. Circulation Research , 120 (5) pp. 784-798. 10.1161/CIRCRESAHA.116.309678. Green open access

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Abstract

RATIONALE: In the endothelium, insulin stimulates endothelial nitric oxide synthase (eNOS) to generate the anti-atherosclerotic signalling radical NO. Insulin resistant type 2 diabetes 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 over-expression 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 Akt was increased in hIRECO EC as was Nox2 NADPH oxidase-dependent generation of superoxide, whereas insulin and shear stress-stimulated eNOS activation were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of PYK2 which phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of PYK2 improved insulin and shear-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 pro-atherosclerotic imbalance between NO and superoxide. Inhibition of PYK2 restores insulin- and shear-induced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a pro-atherosclerotic imbalance between NO and superoxide.

Type: Article
Title: Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signalling Loop
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/CIRCRESAHA.116.309678
Publisher version: http://dx.doi.org/10.1161/CIRCRESAHA.116.309678
Language: English
Additional information: Copyright © 2017 by American Heart Association, Inc.
Keywords: NADPH oxidase, Proline-rich tyrosine kinase, diabetes mellitus, endothelial function, endothelial nitric oxide synthase, insulin, insulin receptor, insulin resistance, nitric oxide, reactive oxygen species
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1533304
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