Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance.

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 (ECSHIP2Δ/+). Hyperinsulinemic-euglycemic clamping studies revealed that ECSHIP2Δ/+ was resistant to insulin-stimulated glucose uptake in adipose tissue and skeletal muscle compared with littermate controls. ECs from ECSHIP2Δ/+ 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 ECSHIP2Δ/+ mice, as was aortic nitric oxide bioavailability. Acetylcholine-induced vasodilation was also impaired in ECSHIP2Δ/+ mice, which was exaggerated in the presence of a superoxide dismutase/catalase mimetic. Superoxide abundance was elevated in ECSHIP2Δ/+ 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.

• Authors: Nicole T Watt, Matthew C Gage, Peysh A Patel, Hema Viswambharan, Piruthivi Sukumar, Stacey Galloway, Nadira Y Yuldasheva, Helen Imrie, Andrew M N Walker, Kathryn J Griffin, Natalia Makava, Anna Skromna, Katherine Bridge, David J Beech, Stéphane Schurmans, Stephen B Wheatcroft, Mark T Kearney, Richard M Cubbon
• Journal: Diabetes (Diabetes) Vol. 66 Issue 11 Pg. 2808-2821 (11 2017) ISSN: 1939-327X [Electronic] United States
• PMID: 28830894 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by the American Diabetes Association.

Chemical References

• Cybb protein, mouse
• NADPH Oxidase 2
• Inppl1 protein, mouse
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases

Topics

• Animals
• Aorta
• Cells, Cultured
• Endothelial Cells
• Endothelium, Vascular (metabolism)
• Gene Expression Regulation (physiology)
• Glucose Clamp Technique
• Glucose Intolerance
• Insulin Resistance (physiology)
• Mice
• Mice, Knockout
• NADPH Oxidase 2 (genetics, metabolism)
• Oxidative Stress (physiology)
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases (genetics, metabolism)
• Vasoconstriction (physiology)