https://scholars.lib.ntu.edu.tw/handle/123456789/383973
標題: | Nε-carboxymethyllysine-mediated endoplasmic reticulum stress promotes endothelial cell injury through Nox4/MKP-3 interaction | 作者: | SHING-HWA LIU | 關鍵字: | AGEs; CML; ERK; Free radicals; Human endothelial cells; MKP-3; Nox4 | 公開日期: | 2014 | 卷: | 74 | 起(迄)頁: | 294-306 | 來源出版物: | Free Radical Biology and Medicine | 摘要: | Nε-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. ? 2014 Elsevier Inc. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84907367024&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/383973 |
DOI: | 10.1016/j.freeradbiomed.2014.06.015 | SDG/關鍵字: | 6 n carboxymethyllysine; acetylcysteine; apocynin; dual specificity phosphatase 6; reduced nicotinamide adenine dinucleotide phosphate oxidase 4; small interfering RNA; thapsigargin; dual specificity phosphatase 6; lysine; N(6)-carboxymethyllysine; NOX4 protein, human; protein binding; reduced nicotinamide adenine dinucleotide phosphate oxidase; small interfering RNA; adult; animal experiment; animal model; apoptosis; article; cell damage; clinical article; controlled study; endoplasmic reticulum stress; endothelium cell; endothelium injury; enzyme activation; female; gene silencing; human; immunohistochemistry; in vitro study; insulin dependent diabetes mellitus; lipid diet; male; microvascular endothelial cell; middle aged; mouse; non insulin dependent diabetes mellitus; nonhuman; priority journal; protein dephosphorylation; protein expression; protein phosphorylation; protein protein interaction; streptozotocin-induced diabetes mellitus; tandem mass spectrometry; umbilical vein endothelial cell; analogs and derivatives; animal; blood; C57BL mouse; chemically induced; drug effects; endothelium cell; experimental diabetes mellitus; gene expression regulation; genetics; metabolism; molecularly targeted therapy; non insulin dependent diabetes mellitus; physiology; signal transduction; transformed cell line; Animals; Apoptosis; Cell Line, Transformed; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Dual Specificity Phosphatase 6; Endoplasmic Reticulum Stress; Endothelial Cells; Gene Expression Regulation; Humans; Lysine; Male; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; NADPH Oxidase; Protein Binding; RNA, Small Interfering; Signal Transduction |
顯示於: | 毒理學研究所 |
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