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

Content Provider	Semantic Scholar
Author	Viswambharan, Hema Yuldasheva, Nadira Y. Sengupta, Anshuman Imrie, Helen Gage, Matthew C. Haywood, N. J. Walker, Andrew Michael Nicholas Skromna, Anna Makova, Natallia Galloway, Stacey L. Shah, Pooja D. Sukumar, P. Ram Porter, Karen E. Grant, Peter John Shah, Ajay M. Santos, Camila Ximenes Li, Jing He Beech, David J. Wheatcroft, Stephen B. Cubbon, Richard M. Kearney, Mark T.
Copyright Year	2017
Abstract	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.
Starting Page	784
Ending Page	798
Page Count	15
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Alternate Webpage(s)	http://eprints.whiterose.ac.uk/109437/1/CIRCRES-309678D%20R1%20Manuscript.pdf
Alternate Webpage(s)	http://circres.ahajournals.org/content/circresaha/120/5/784.full.pdf
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Alternate Webpage(s)	http://eprints.whiterose.ac.uk/109437/6/Suppl%20Fig%20CIRCRES-309678_R1.pdf
PubMed reference number	27920123v1
Alternate Webpage(s)	https://doi.org/10.1161/CIRCRESAHA.116.309678
DOI	10.1161/CIRCRESAHA.116.309678
Journal	Circulation research
Volume Number	120
Issue Number	5
Language	English
Access Restriction	Open
Subject Keyword	Acetylcholine Amine Oxidase (Copper-Containing) Atherosclerosis Diabetes Mellitus Diabetes Mellitus, Non-Insulin-Dependent Endothelial Cells Endothelium Insulin L-Epicatechin NADPH Oxidase NOS3 gene NOS3 protein, human Nitric Oxide Synthase Proline Protein Kinases Superoxides TYK2 Kinase Tyrosine Phosphorylation Vasodilation insulin, isophane protein tyrosine kinase PYK2 shear stress
Content Type	Text
Resource Type	Article