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

Carlos Zaragoza, Estrella Soria, Esther López, Darren Browning, Milagros Balbín, Carlos López-Otín, Santiago Lamas

Research output: Contribution to journalArticle

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Abstract

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,N2-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-α 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-α and the G-protein Raf-1, an upstream activator of the extracellular signal-regulated kinase signaling pathway, was detected in cells overexpressing PKG1-α 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 the result of pathophysiological importance in the context of inflammation or atherogenesis.

Original languageEnglish (US)
Pages (from-to)927-935
Number of pages9
JournalMolecular Pharmacology
Volume62
Issue number4
DOIs
StatePublished - Oct 2002

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Matrix Metalloproteinase 13
Cyclic GMP-Dependent Protein Kinases
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinases
Nitric Oxide
Endothelial Cells
Oxides
Nitric Oxide Donors
Guanylate Cyclase
Nucleic Acid Regulatory Sequences
Extracellular Signal-Regulated MAP Kinases
Protein Kinase Inhibitors
Matrix Metalloproteinases
Mitogens
GTP-Binding Proteins
Growth Hormone
Catalytic Domain
Atherosclerosis
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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. / Zaragoza, Carlos; Soria, Estrella; López, Esther; Browning, Darren; Balbín, Milagros; López-Otín, Carlos; Lamas, Santiago.

In: Molecular Pharmacology, Vol. 62, No. 4, 10.2002, p. 927-935.

Research output: Contribution to journalArticle

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AU - López-Otín, Carlos

AU - Lamas, Santiago

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