title: Inhibition of plasmin-mediated prostromelysin-1 activation by interaction of long chain unsaturated fatty acids with kringle 5.
abstract: C18 unsaturated fatty acids were here found to inhibit proMMP (matrix metalloproteinase)-3 activation by plasmin. This effect was suppressed by lysine ligand competitors, indicating that it was mediated by binding to kringle domains. Surface plasmon resonance analysis demonstrated that oleic acid interacted to a similar extent with plasmin and kringle 5 (KD values of 3.4 x 10(-8) and 5.9 x 10(-8)M) while interaction with kringles 1-2-3 was 10-fold lower. Furthermore, oleic acid stimulated the amidolytic activity of plasmin and mini-plasmin, but not micro-plasmin. Oleic acid also enhanced u-PA (urokinase-type plasminogen activator)-mediated plasminogen activation over 50-fold. Taken together, these data indicate that inhibition of plasmin-induced proMMP-3 activation by unsaturated fatty acids was mediated through their preferential binding to kringle 5. The influence of elaidic acid on the plasmin/MMP-3/MMP-1 proteolytic cascade was assessed ex vivo. Exogenous addition of plasmin to dermal fibroblasts or supplementation of gingival fibroblast culture medium with plasminogen triggered this cascade. In both instances, elaidic acid totally abolished proMMP-3 and proMMP-1 activation. Additionally, a significant decrease in lattice retraction and collagen degradation in a range similar to that obtained with Batimastat was observed when human gingival fibroblasts were cultured in plasminogen-containing type I collagen gels, indicative of the dual influence of unsaturated fatty acids on MMP activation and activity. In conclusion, unsaturated fatty acids or molecules with similar structures could be attractive target for the development of natural pharmacological inhibitors directed against plasmin and/or MMPs in different pathological contexts such, skin UV irradiation, vascular diseases and tumour growth and invasion.
authors.affiliation: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, London W6 8LH, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Huet
authors.forename: Jean-Hubert
authors.initials: JH
authors.lastname: Cauchard
authors.forename: Alix
authors.initials: A
authors.lastname: Berton
authors.forename: Arnaud
authors.initials: A
authors.lastname: Robinet
authors.forename: Martine
authors.initials: M
authors.lastname: Decarme
authors.forename: William
authors.initials: W
authors.lastname: Hornebeck
authors.forename: Georges
authors.initials: G
authors.lastname: Bellon
mesh_terms: D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005341:Fibrinolysin / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018082:Kringles; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D004792:Enzyme Precursors; D005231:Fatty Acids, Unsaturated; D061965:Matrix Metalloproteinase Inhibitors; D010958:Plasminogen; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases; C048047:prostromelysin; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1