Elastokine-mediated up-regulation of MT1-MMP is triggered by nitric oxide in endothelial cells

• Published in: The international journal of biochemistry & cell biology Vol. 40; no. 8; pp. 1581 - 1596
• Main Authors: Fahem, A., Robinet, A., Cauchard, J.H., Duca, L., Soula-Rothhut, M., Rothhut, B., Soria, C., Guenounou, M., Hornebeck, W., Bellon, G.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-01-2008; Elsevier
• Subjects: Cell Line; Chromones - pharmacology; Elastin - pharmacology; Elastokines; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; Matrix Metalloproteinase 14 - biosynthesis; Mitogen-Activated Protein Kinase 1 - physiology; Mitogen-Activated Protein Kinase 3 - physiology; Morpholines - pharmacology; MT1-MMP; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide - physiology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - physiology; Oligopeptides - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology; Signal Transduction - drug effects; Signaling pathway; Up-Regulation; NO; HMEC; PIP 3; VEGF; HRP; ECGM MV; Elastokines; ECM; sGC; Endothelial cells; MMP; MT1-MMP; NOS; ECGS/H; Signaling pathway; (p)MT1-MMP; Nitric oxide; FCS; V-18; KE; V-14; (p)MMP2
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2007.11.022

Membrane-type I matrix metalloproteinase (MT1-MMP) has been previously reported to be up-regulated in human microvascular endothelial cell-1 line (HMEC) by elastin-derived peptides (elastokines). The aim of the present study was to identify the signaling pathways responsible for this effect. We showed that elastokines such as (VGVAPG)
3 peptide and kappa elastin induced nitric oxide (NO) production in a time-, concentration- and receptor-dependent manner as it could be abolished by lactose and a receptor-derived competitive peptide. As evidenced by the use of NO synthase inhibitors, elastokine-mediated up-regulation of MT1-MMP and pseudotube formation on Matrigel required NO production through activation of the PI
3-kinase/Akt/NO synthase and NO/cGMP/Erk1/2 pathways. Elastokines induced both PI
3-kinase p110γ sub-unit, Akt and Erk1/2 activation, as shown by a transient increase in phospho-Akt and phospho-Erk1/2, reaching a maximum after 5 and 15
min incubation, respectively. Inhibitors of PI
3-kinase and MEK1/2 suppressed elastokine-mediated MT1-MMP expression at both the mRNA and protein levels, and decreased the ability of elastokines to accelerate pseudotube formation. Besides, elastokines mediated a time- and concentration-dependent increase of cGMP, suggesting a link between NO and MT1-MMP expression. This was validated by the use of a guanylyl cyclase inhibitor, a NO donor and a cGMP analog. The guanylyl cyclase inhibitor abolished the stimulatory effect of elastokines on MT1-MMP expression. Inversely, the cGMP analog, mimicked the effect of both elastokines and NO donor in a concentration- and time-dependent manner. Overall, our results demonstrated that such elastokine properties through NO and MT1-MMP may be of importance in the context of tumour progression.