Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop
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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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The flavoprotein domain binds the cofactor FAD and includes a binding site for NADPH.
“The transmembrane domain includes four conserved histidines that serve as binding sites for two heme moieties bound between helices III and V (288, 613), and the flavoprotein domain binds the cofactor FAD and includes a binding site for NADPH (49, 480, 613, 980).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [980]
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- Authors
- Viswambharan, H., Yuldasheva, N. Y., Sengupta, A., Imrie, H., Gage, M. C., Haywood, N., Walker, A. M. N., Skromna, A., Makova, N., Galloway, S., Shah, P., Sukumar, P., Porter, K. E., Grant, P. J., Shah, A. M., Santos, C. X. C., Li, J., Beech, D. J., Wheatcroft, S. B., Cubbon, R. M., & Kearney, M. T.
- Affiliations
- University of Leeds (GB)
- From 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.).
- ORCID
- Venue
- Circulation Research
- Published
- 2017-03-03
- Volume
- 120
- Issue
- 5
- Pages
- 784-798
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2559952161
- Cited by
- 43
- References
- 45
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 6 · 2017: 8
- FWCI
- 4.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute for Health and Care Research (ACF-2017-02-009)
- British Heart Foundation (RG/15/7/31521, RG/09/010/28087, FS/14/10/30472, FS/12/80/29821, RG/13/11/30384, FS/11/94/29180)
- Academy of Medical Sciences (AMS-SGCL6-Cubbon)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- endothelial dysfunction, endothelial nitric oxide synthase, Pyk2, NADPH oxidase 2, superoxide, nitric oxide, shear stress, Akt, type 2 diabetes, atherosclerosis, endothelium-dependent relaxation
- MeSH terms
- Animals, Cells, Cultured, Endothelium, Vascular, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Transgenic, Organ Culture Techniques, Signal Transduction, Endothelial Cells, Atherosclerosis, Mice, Mice, 129 Strain, Human Umbilical Vein Endothelial Cells
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