Advanced glycation end product Nε-carboxymethyllysine induces endothelial cell injury: the involvement of SHP-1-regulated VEGFR-2 dephosphorylation
| Autor: | Shing Hwa, Liu, Wayne Huey Herng, Sheu, Maw Rong, Lee, Wen Jane, Lee, Yu Chiao, Yi, Tzung Jie, Yang, Jen Fon, Jen, Hung Chuan, Pan, Chin Chang, Shen, Wen Bao, Chen, Hsing Ru, Tien, Meei Ling, Sheu |
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| Rok vydání: | 2011 |
| Předmět: |
Glycation End Products
Advanced Male Lysine Protein Tyrosine Phosphatase Non-Receptor Type 6 Transfection Vascular Endothelial Growth Factor Receptor-2 Diabetes Mellitus Experimental Mice Inbred C57BL Mice Human Umbilical Vein Endothelial Cells Animals Humans Endothelium Vascular Gene Silencing Phosphorylation RNA Small Interfering Reactive Oxygen Species Aorta |
| Zdroj: | The Journal of pathology. 230(2) |
| ISSN: | 1096-9896 |
| Popis: | 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 and ROS production. The CML-increased SHP-1 activity in HUVECs was effectively attenuated by antioxidants. Moreover, the immunohistochemical staining of SHP-1 and CML was increased, but phospho-VEGFR-2 staining was decreased in the aortic endothelium of streptozotocin-induced and high-fat diet-induced diabetic mice. We conclude that a pathway of tyrosine phosphatase SHP-1-regulated VEGFR-2 dephosphorylation through NADPH oxidase-derived ROS is involved in the CML-triggered endothelial cell dysfunction/injury. These findings suggest new insights into the development of therapeutic approaches to reduce diabetic vascular complications. |
| Databáze: | OpenAIRE |
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