Watt, NT;
Gage, MC;
Patel, PA;
Viswambharan, H;
Sukumar, P;
Galloway, S;
Yuldasheva, NY;
... Cubbon, RM; + view all
(2017)
Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction and Systemic Insulin Resistance.
Diabetes
, 66
(1)
pp. 2808-2821.
10.2337/db17-0062.
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Abstract
Shc homology 2-containing inositol 5´ phosphatase-2 (SHIP2) is as lipid phosphatase which inhibits insulin signaling downstream of phosphoinositide-3-kinase (PI3K); its role in vascular function is poorly understood. To examine its role in endothelial cell (EC) biology, we generated mice with catalytic inactivation of one SHIP2 allele selectively in EC (ECSHIP2(Δ/+)). Hyperinsulinemic euglycemic clamping studies revealed ECSHIP2(Δ/+) were resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle, compared with littermate controls. EC from ECSHIP2(Δ/+) had increased basal expression and activation of PI3K downstream targets, including Akt and endothelial nitric oxide synthase (eNOS), although incremental activation by insulin and shear stress was impaired. Insulin-mediated vasodilation was blunted in ECSHIP2(Δ/+), as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2(Δ/+), which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2(Δ/+) EC, and was suppressed by PI3K and Nox2 NADPH oxidase inhibitors. These findings were phenocopied in healthy human EC after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required to maintain normal systemic glucose homeostasis and prevent oxidative stress-induced endothelial dysfunction.
| Type: | Article |
|---|---|
| Title: | Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction and Systemic Insulin Resistance. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.2337/db17-0062 |
| Publisher version: | https://doi.org/10.2337/db17-0062 |
| Language: | English |
| Additional information: | © 2017 by the American Diabetes Association. http://www.diabetesjournals.org/content/license Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| 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/1571562 |
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