Nε-carboxymethyllysine-mediated endoplasmic reticulum stress promotes endothelial cell injury through Nox4/MKP-3 interaction
| Autor: | Yi-Ching Tsai, Chin-Chang Shen, Shih-Yi Lin, Meei-Ling Sheu, Wei-Chih Chen, Tzung-Jie Yang, Kae-Woei Liang, Wayne Huey-Herng Sheu, Maw-Rong Lee, Li-Yun Lin, Hsiang-Yu Yeh, Shing-Hwa Liu, Hsing-Ru Tien, Wen-Jane Lee, Yu-Chiao Yi |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Male Apoptosis Protein tyrosine phosphatase Biology Diet High-Fat Biochemistry Diabetes Mellitus Experimental Dephosphorylation Mice Dual Specificity Phosphatase 6 hemic and lymphatic diseases Physiology (medical) Animals Humans Molecular Targeted Therapy RNA Small Interfering Cell Line Transformed Endoplasmic reticulum Lysine NOX4 Endothelial Cells NADPH Oxidases Endoplasmic Reticulum Stress Endothelial stem cell Mice Inbred C57BL Diabetes Mellitus Type 2 Gene Expression Regulation NADPH Oxidase 4 Immunology Cancer research Unfolded protein response Signal transduction Protein Binding Signal Transduction |
| Zdroj: | Free radical biologymedicine. 74 |
| ISSN: | 1873-4596 |
| Popis: | N(e)-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect