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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
Liu, Shing-Hwa
Yi, Yu-Chiao
Chen, Wei-Chih
Lin, Shih-Yi
Liang, Kae-Woei
Shen, Chin-Chang
Yeh, Hsiang-Yu
Lin, Li-Yun
Tsai, Yi-Ching
Tien, Hsing-Ru
Lee, Maw-Rong
Yang, Tzung-Jie
Sheu, Meei-Ling
關鍵字: AGEs
Free radicals
Human endothelial cells
Cell Line, Transformed
Diabetes Mellitus, Experimental
Diabetes Mellitus, Type 2
Diet, High-Fat
Dual Specificity Phosphatase 6
Endothelial Cells
Gene Expression Regulation
Mice, Inbred C57BL
Molecular Targeted Therapy
NADPH Oxidase
Protein Binding
RNA, Small Interfering
Signal Transduction
Endoplasmic Reticulum Stress
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.
ISSN: 08915849
Appears in Collections:生物醫學研究所



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