Activation of the mitogen activated protein kinase extracellular signal-regulated kinase 1 and 2 by the nitric oxide-cGMP-cGMP-dependent protein kinase axis regulates the expression of matrix metalloproteinase 13 in vascular endothelial cells
| Autor: | Darren D Browning, Santiago Lamas, Carlos Zaragoza, Esther López, Estrella Soria, Carlos López-Otín, Milagros Balbín |
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| Rok vydání: | 2002 |
| Předmět: |
Transcription
Genetic Mitogen-activated protein kinase kinase Nitric Oxide Gene Expression Regulation Enzymologic MAP2K7 Mice Matrix Metalloproteinase 13 Animals ASK1 Nitric Oxide Donors c-Raf Collagenases Cyclic GMP Cells Cultured Pharmacology Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 MAP kinase kinase kinase Chemistry Akt/PKB signaling pathway Macrophages Molecular biology Cell biology Enzyme Activation Hydrazines Molecular Medicine Cyclin-dependent kinase 9 Cattle Nitrogen Oxides Endothelium Vascular Mitogen-Activated Protein Kinases cGMP-dependent protein kinase Protein Kinases |
| Zdroj: | Molecular pharmacology. 62(4) |
| ISSN: | 0026-895X |
| Popis: | Matrix metalloproteinases (MMPs) are synthesized in response to diverse stimuli, including cytokines, growth factors, hormones, and oxidative stress. Here we show that the nitric oxide (NO) donor 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA-NO) and NO from murine macrophages transcriptionally regulate MMP-13 expression in vascular endothelial cells (BAEC). The cGMP analog, 8-bromo-cGMP (8-Br-cGMP) mimicked the effect of NO, whereas incubation with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or the cGMP-dependent protein kinase (PKG) inhibitor phenyl-1,N (2)- etheno-8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (PET) reduced the stimulatory effect of DEA-NO on the activation of the MMP-13 promoter. Overexpression of the catalytic subunit of PKG1-alpha resulted in a 5- to 6-fold increase of the MMP-13 regulatory region over control cells. On the other hand, incubation with the mitogen-activated protein/extracellular signal-regulated kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) significantly reduced DEA-NO and 8-Br-cGMP promoter activation and mRNA expression of MMP-13 in transfected BAEC. Moreover, a complex between PKG1-alpha and the G-protein Raf-1, an upstream activator of the extracellular signal-regulated kinase signaling pathway, was detected in cells overexpressing PKG1-alpha or treated either with DEA-NO or 8-Br-cGMP. Thus, we propose that the NO-cGMP-PKG pathway enhances MMP-13 expression by the activation of ERK 1,2. This effect of NO may be important in the context of pathophysiological conditions such as inflammation or atherogenesis [corrected]. |
| Databáze: | OpenAIRE |
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