Article (Scientific journals)
Endothelial SHIP2 suppresses Nox2 NADPH oxidase-dependent vascular oxidative stress, endothelial dysfunction and systemic insulin resistance
Watt, NT; Gage, MC; Patel, PA et al.
2017In Diabetes, 66 (11), p. 2808-2821
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Keywords :
Ship2; endothelial cell; insulin
Abstract :
[en] 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 (ECSHIP2Δ/+). Hyperinsulinemic euglycemic clamping studies revealed ECSHIP2Δ/+ were resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle, compared with littermate controls. EC from ECSHIP2Δ/+ 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 ECSHIP2Δ/+, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2Δ/+, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2Δ/+ 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Watt, NT
Gage, MC
Patel, PA
Viswambharan, H
Sukumar, P
Galloway, S
Yuldasheva, NY
Imrie, H
Walker, AMN
Griffin, KJ
Makava, N
Skromna, A
Bridge, K
Beech, DJ
Schurmans, Stéphane  ;  Université de Liège > Département des sciences fonctionnelles (DSF) > Biochimie métabolique vétérinaire
Wheatcroft, SB
Kearney, MT
Cubbon, RM
More authors (8 more) Less
Language :
English
Title :
Endothelial SHIP2 suppresses Nox2 NADPH oxidase-dependent vascular oxidative stress, endothelial dysfunction and systemic insulin resistance
Publication date :
2017
Journal title :
Diabetes
ISSN :
0012-1797
eISSN :
1939-327X
Publisher :
American Diabetes Association, Alexandria, United States - Virginia
Volume :
66
Issue :
11
Pages :
2808-2821
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 24 August 2017

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