Advanced glycation end product Nε-carboxymethyllysine induces endothelial cell injury: the involvement of SHP-1-regulated VEGFR-2 dephosphorylation

The Journal of Pathology
Shing Hwa LiuMeei Ling Sheu

Abstract

N(ε)-carboxymethyllysine (CML), a major advanced glycation end product, plays a crucial role in diabetes-induced vascular injury. The roles of protein tyrosine phosphatases and vascular endothelial growth factor (VEGF) receptors in CML-related endothelial cell injury are still unclear. Human umbilical vein endothelial cells (HUVECs) are a commonly used human EC type. Here, we tested the hypothesis that NADPH oxidase/reactive oxygen species (ROS)-mediated SH2 domain-containing tyrosine phosphatase-1 (SHP-1) activation by CML inhibits the VEGF receptor-2 (VEGFR-2, KDR/Flk-1) activation, resulting in HUVEC injury. CML significantly inhibited cell proliferation and induced apoptosis and reduced VEGFR-2 activation in parallel with the increased SHP-1 protein expression and activity in HUVECs. Adding recombinant VEGF increased forward biological effects, which were attenuated by CML. The effects of CML on HUVECs were abolished by SHP-1 siRNA transfection. Exposure of HUVECs to CML also remarkably escalated the integration of SHP-1 with VEGFR-2. Consistently, SHP-1 siRNA transfection and pharmacological inhibitors could block this interaction and elevating [(3)H]thymidine incorporation. CML also markedly activated the NADPH oxidase an...Continue Reading

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Citations

Sep 15, 2014·Archives of Dermatological Research·Yoriko NishikoriHideki Okunishi
Jan 20, 2016·Journal of Diabetes and Its Complications·Xinjuan SunAiping Wang
Dec 24, 2015·PloS One·Trine M ReineSvein O Kolset
Mar 30, 2019·Journal of Biochemical and Molecular Toxicology·Yi-Xin WangZhi-Yong Gong
Nov 11, 2017·The Journal of Clinical Endocrinology and Metabolism·Eugene J BarrettCarolina M Casellini
Nov 13, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Wayne Huey-Herng SheuMeei-Ling Sheu

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