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Publication
Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative
Stress, Endothelial Dysfunction, and Systemic Insulin Resistance.
Authors 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 S, Wheatcroft SB, Kearney MT, Cubbon RM
Submitted By Submitted Externally on 8/6/2018
Status Published
Journal Diabetes
Year 2017
Date Published 11/1/2017
Volume : Pages 66 : 2808 - 2821
PubMed Reference 28830894
Abstract Shc homology 2-containing inositol 5' phosphatase-2 (SHIP2) is a lipid
phosphatase that inhibits insulin signaling downstream of phosphatidylinositol
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 ECs (ECSHIP2?/+).
Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2?/+ was
resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal
muscle compared with littermate controls. ECs from ECSHIP2?/+ mice had increased
basal expression and activation of PI3K downstream targets, including Akt and
endothelial nitric oxide synthase, although incremental activation by insulin
and shear stress was impaired. Insulin-mediated vasodilation was blunted in
ECSHIP2?/+ mice, as was aortic nitric oxide bioavailability.
Acetylcholine-induced vasodilation was also impaired in ECSHIP2?/+ mice, which
was exaggerated in the presence of a superoxide dismutase/catalase mimetic.
Superoxide abundance was elevated in ECSHIP2?/+ ECs and was suppressed by PI3K
and NADPH oxidase 2 inhibitors. These findings were phenocopied in healthy human
ECs after SHIP2 silencing. Our data suggest that endothelial SHIP2 is required
to maintain normal systemic glucose homeostasis and prevent oxidative
stress-induced endothelial dysfunction.








Genes
SymbolDescription
Inppl1inositol polyphosphate phosphatase-like 1

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