Endothelial SHIP2 suppresses Nox2 NADPH oxidase-dependent vascular oxidative stress, endothelial dysfunction and systemic insulin resistance

Watt, N T; Gage, M C; Patel, P A; Viswambharan, H; Sukumar, P; Galloway, S; Yuldasheva, N Y; Imrie, H; Walker, A M N; Griffin, K J; Makava, N; Skromna, A; Bridge, K; Beech, D J; Schurmans, S; Wheatcroft, S B; Kearney, M T; Cubbon, R M

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.

Citation

Watt, N. T., Gage, M. C., Patel, P. A., Viswambharan, H., Sukumar, P., Galloway, S., …Cubbon, R. M. (2017). Endothelial SHIP2 suppresses Nox2 NADPH oxidase-dependent vascular oxidative stress, endothelial dysfunction and systemic insulin resistance. Diabetes, 66(11), 2808-2821. https://doi.org/10.2337/db17-0062

• Journal Article Type: Article
• Acceptance Date: Aug 4, 2017
• Publication Date: Aug 4, 2017
• Deposit Date: May 29, 2019
• Publicly Available Date: Nov 21, 2020
• Journal: DIABETES
• Print ISSN: 0012-1797
• Publisher: American Diabetes Association
• Peer Reviewed: Peer Reviewed
• Volume: 66
• Issue: 11
• Pages: 2808-2821
• DOI: https://doi.org/10.2337/db17-0062
• Public URL: https://rvc-repository.worktribe.com/output/1390944