Shark cartilage extract induces cytokines expression and release in endothelial cells and induces E-selectin, plasminogen and t-PA genes expression through an antioxidant-sensitive mechanism.
Neovastat® is a standardized extract of marine cartilage, an avascular tissue, which contains many biologically active molecules and has multiple antiangiogenic properties. In addition to VEGFR2 and MMPs inhibition, shark cartilage extract (SCE) has recently been shown to induce tissue plasminogen activator gene (PLAT) expression in bovine endothelial cells in a TNF like manner, by inducing the typical mediators NF-κB and JNK. There is now compelling evidences that the NF-κB and JNK pathways are activated by cytokines induced generation of reactive oxygen species (ROS). We used macroarray genes expression analysis on human umbilical vein endothelial cells, to investigate if that mechanism could mediate the effect of SCE. Transcriptomic results showed that SCE induced expression of several cytokines. Their impact must be important, given that treatment of endothelial cells with the cytokine TNF-α was able to reproduce most of the effects of cartilage extract on genes expression. In addition, most of the genes, known to be inducible by NF-κB or JNK following cytokines stimulation, were less induced by SCE when endothelial cells were pretreated with the antioxidant N-Acetylcysteine (NAC), suggesting a role of ROS in endothelial cell activation by SCE. Finally, the possible effects of PLAT, PLG, SELE, IL8 and PRDX2 (those validated by q-PCR) on angiogenesis, will also be discussed.
Grenoble Institut des Neurosciences, INSERM U 836, Équipe 7, BP 170, F38042 Grenoble Cedex 9, France. simardbryan@yahoo.com
Bryan
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Simard
David
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Ratel
Isabelle
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Dupré
Virginie
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Pautre
François
F
Berger
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D019040:E-Selectin / Q000096:biosynthesis*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010958:Plasminogen / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014020:Tissue Extracts / Q000378:metabolism / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
D000975:Antioxidants; D016207:Cytokines; D019040:E-Selectin; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014020:Tissue Extracts; D014409:Tumor Necrosis Factor-alpha; C111481:shark cartilage extract; D010958:Plasminogen; D048031:JNK Mitogen-Activated Protein Kinases; D010959:Tissue Plasminogen Activator; D000111:Acetylcysteine