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

Hema Viswambharan*, Nadira Y. Yuldasheva, Anshuman Sengupta, Helen Imrie, Matthew C. Gage, Natalie Haywood, Andrew M N Walker, Anna Skromna, Natallia Makova, Stacey Galloway, Pooja Shah, Piruthivi Sukumar, Karen E. Porter, Peter J. Grant, Ajay Shah, Celio X. Santos, Jing Li, David J. Beech, Stephen B. Wheatcroft, Richard M. CubbonMark T. Kearney

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)784-798
Number of pages15
JournalCirculation Research
Volume120
Issue number5
DOIs
Publication statusPublished - 3 Mar 2017

Keywords

  • diabetes mellitus
  • insulin
  • insulin resistance
  • reactive oxygen species
  • superoxide

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