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|標題:||Nε-carboxymethyllysine-mediated endoplasmic reticulum stress promotes endothelial cell injury through Nox4/MKP-3 interaction||作者:||Lee, Wen-Jane
Huey-Herng Sheu, Wayne
|關鍵字:||AGEs;CML;ERK;Free radicals;Human endothelial cells;MKP-3;Nox4;Animals;Apoptosis;Cell Line, Transformed;Diabetes Mellitus, Experimental;Diabetes Mellitus, Type 2;Diet, High-Fat;Dual Specificity Phosphatase 6;Endothelial Cells;Gene Expression Regulation;Humans;Lysine;Male;Mice;Mice, Inbred C57BL;Molecular Targeted Therapy;NADPH Oxidase;Protein Binding;RNA, Small Interfering;Signal Transduction;Endoplasmic Reticulum Stress||Project:||Free Radical Biology and Medicine, Volume 74, Page(s) 294-306.||摘要:||
N(ε)-carboxymethyllysine (CML) is an important driver of diabetic vascular complications and endothelial cell dysfunction. However, how CML dictates specific cellular responses and the roles of protein tyrosine phosphatases and ERK phosphorylation remain unclear. We examined whether endoplasmic reticulum (ER) localization of MAPK phosphatase-3 (MKP-3) is critical in regulating ERK inactivation and promoting NADPH oxidase-4 (Nox4) activation in CML-induced endothelial cell injury. We demonstrated that serum CML levels were significantly increased in type 2 diabetes patients and diabetic animals. CML induced ER stress and apoptosis, reduced ERK activation, and increased MKP-3 protein activity in HUVECs and SVECs. MKP-3 siRNA transfection, but not that of MKP-1 or MKP-2, abolished the effects of CML on HUVECs. Nox4-mediated activation of MKP-3 regulated the switch to ERK dephosphorylation. CML also increased the integration of MKP-3 with ERK, which was blocked by silencing MKP-3. Exposure of antioxidants abolished CML-increased MKP-3 activity and protein expression. Furthermore, immunohistochemical staining of both MKP-3 and CML was increased, but phospho-ERK staining was decreased in the aortic endothelium of streptozotocin-induced and high-fat diet-induced diabetic mice. Our results indicate that an MKP-3 pathway might regulate ERK dephosphorylation through Nox4 during CML-triggered endothelial cell dysfunction/injury, suggesting that therapeutic strategies targeting the Nox4/MKP-3 interaction or MKP-3 activation may have clinical implications for diabetic vascular complications.
|Appears in Collections:||生物醫學研究所|
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