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Nε-carboxymethyllysine-mediated endoplasmic reticulum stress promotes endothelial cell injury through Nox4/MKP-3 interaction.
Lee, Wen-Jane; Sheu, Wayne Huey-Herng; 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.
Afiliação
  • Lee WJ; Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Social Work, Tunghai University, Taichung, Taiwan.
  • Sheu WH; Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan; Rong Hsing Research Center for Translational Medicine, and National Chung Hsing University, Taichung 402, Taiwan.
  • Liu SH; Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • Yi YC; Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan.
  • Chen WC; Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan.
  • Lin SY; Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
  • Liang KW; Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
  • Shen CC; Institute of Nuclear Energy Research, Atomic Energy Council, Longtan, Taoyuan, Taiwan.
  • Yeh HY; Department of Nutrition and Institute of Biomedical Nutrition and Hung-Kuang University, Taichung, Taiwan.
  • Lin LY; Department of Food and Nutrition, Hung-Kuang University, Taichung, Taiwan.
  • Tsai YC; Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan.
  • Tien HR; Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan.
  • Lee MR; Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan.
  • Yang TJ; Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan.
  • Sheu ML; Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan; Rong Hsing Research Center for Translational Medicine, and National Chung Hsing University, Taichung 402, Taiwan. Electronic
Free Radic Biol Med ; 74: 294-306, 2014 Sep.
Article em En | MEDLINE | ID: mdl-25014566
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: NADPH Oxidases / Células Endoteliais / Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 / Fosfatase 6 de Especificidade Dupla / Estresse do Retículo Endoplasmático / Lisina Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: NADPH Oxidases / Células Endoteliais / Diabetes Mellitus Experimental / Diabetes Mellitus Tipo 2 / Fosfatase 6 de Especificidade Dupla / Estresse do Retículo Endoplasmático / Lisina Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2014 Tipo de documento: Article