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* Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, Québec H1T 2M4 Canada;
Perinatal Research Centre, and
Laboratory of Mass Spectrometry, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2S2 Canada
2Correspondence: Research Center, Maisonneuve-Rosemont Hospital, University of Montréal, 5415 boulevard de lAssomption, Montréal, Québec H1T 2M4 Canada. E-mail: janos.g.filep{at}umontreal.ca
We recently reported that matrix metalloproteinase 2 (MMP-2, gelatinase A) cleaves big endothelin 1 (ET-1), yielding the vasoactive peptide ET-1[132]. We tested whether ET-1[132] could affect the adhesion of human neutrophils to coronary artery endothelial cells (HCAEC). ET-1[132] rapidly down-regulated the expression of L-selectin and up-regulated expression of CD11b/CD18 on the neutrophil surface, with EC50 values of 13 nM. These actions of ET-1[132] were mediated via ETA receptors and did not require conversion of ET-1[132] into ET-1 by neutrophil proteases, as revealed by liquid chromatography and mass spectroscopy. Moreover, ET-1[132] evoked release of neutrophil gelatinase B, which cleaved big ET-1 to yield ET-1[132], thus revealing a positive feedback loop for ET-1[132] generation. Up-regulation of CD11b/CD18 expression and gelatinase release was tightly associated with activation of extracellular signal-regulated kinase (Erk). Stimulation of Erk activity was due to activation of Ras, Raf-1, and MEK (MAPK kinase). ET-1[132] also produced slight increases in the expression of ICAM-1 and E-selectin on HCAEC, and markedly enhanced ß2 integrin-dependent adhesion of neutrophils to activated HCAEC. These results are the first indication that gelatinolytic MMPs via cleavage of big ET-1 to yield ET-1[132] activate neutrophils and promote leukocyte-endothelial cell adhesion and, consequently, neutrophil trafficking into inflamed tissues.Fernandez-Patron, C., Zouki, C., Whittal, R., Chan, J. S. D., Davidge, S. T., Filep, J. G. Matrix metalloproteinases regulate neutrophil-endothelial cell adhesion through generation of endothelin- 1[132].
Key Words: gelatinases ETA receptor L-selectin CD11b/CD18 leukocyte trafficking endothelium inflammation
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