PF4 inhibits thrombin-stimulated MMP-1 and MMP-3 metalloproteinase expression in human vascular endothelial cells.
We investigated whether PF4 could regulate the constitutive and thrombin-stimulated expression of metalloproteinases (MMPs) in endothelial cells (EC). PF4 inhibited the increase in the expression of MMP-1 and MMP-3 promoted by thrombin or the thrombin receptor agonist peptide SFLLRNPNDKYEPF (SFLL..) by 50% but did not modify the constitutive expression of these MMPs. This inhibitory effect was not mediated through a direct interaction of PF4 with thrombin or with the MMPs themselves. The interaction of PF4 with heparan sulfates at the surface of the EC appeared to be implicated in the inhibition mechanism of MMP-1 but not in that of MMP-3. MMP-1 transcription levels remained unchanged after PF4 treatment, whereas the increase in MMP-3 transcription induced by thrombin or SFLL.. was inhibited by approximately 50%. Expression of the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 was not affected by PF4. The present data provide new evidence that the antiangiogenic properties of PF4 involve the inhibition of matrix breakdown and suggest that this property of PF4 could be especially relevant in the context of thrombin-regulated tissue remodelling.
Klein-Soyer
C
C
Inserm U 311, Etablissement de transfusion sanguine de Strasbourg.
Duhamel-Clérin
E
E
Ravanat
C
C
Orvain
C
C
Lanza
F
F
Cazenave
J P
JP
D015153:Blotting, Western; D003029:Coagulants / Q000494:pharmacology*; D017364:Collagenases / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D008323:Mammary Arteries / Q000201:enzymology; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D010978:Platelet Factor 4 / Q000494:pharmacology*; D012501:Saphenous Vein / Q000201:enzymology; D013268:Stimulation, Chemical; D013917:Thrombin / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects / Q000378:metabolism
D003029:Coagulants; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D010978:Platelet Factor 4; D013917:Thrombin; D017364:Collagenases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D019763:Heparin Lyase