Published online before print September 14, 2007

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(American Journal of Pathology. 2007;171:1713-1723.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070021

Microparticles of Human Atherosclerotic Plaques Enhance the Shedding of the Tumor Necrosis Factor- Converting Enzyme/ADAM17 Substrates, Tumor Necrosis Factor and Tumor Necrosis Factor Receptor-1

Matthias Canault^*, Aurélie S. Leroyer, Franck Peiretti^*, Guy Lesèche, Alain Tedgui, Bernadette Bonardo^*, Marie-Christine Alessi^*, Chantal M. Boulanger and Gilles Nalbone^*

From INSERM, U626,^* Marseille; the Université de la Méditerranée, Marseille; INSERM, U689, Centre de Recherche Cardiovasculaire Lariboisière, Paris; and the Hôpital Beaujon, Clichy, France

Human atherosclerotic plaques express the metalloprotease tumor necrosis factor (TNF)- converting enzyme (TACE/ADAM-17), which cleaves several transmembrane proteins including TNF and its receptors (TNFR-1 and TNFR-2). Plaques also harbor submicron vesicles (microparticles, MPs) released from plasma membranes after cell activation or apoptosis. We sought to examine whether TACE/ADAM17 is present on human plaque MPs and whether these MPs would affect TNF and TNFR-1 cellular shedding. Flow cytometry analysis detected 12,867 ± 2007 TACE/ADAM17⁺ MPs/mg of plaques isolated from 25 patients undergoing endarterectomy but none in healthy human internal mammary arteries. Plaque MPs harbored mainly mature active TACE/ADAM17 and dose dependently cleaved a pro-TNF mimetic peptide, whereas a preferential TACE/ADAM17 inhibitor (TMI-2) and recombinant TIMP-3 prevented this cleavage. Plaque MPs increased TNF shedding from the human cell line ECV-304 overexpressing TNF (ECV-304_TNF), as well as TNFR-1 shedding from activated human umbilical vein endothelial cells or ECV-304_TNF cells, without affecting TNF or TNFR-1 synthesis. MPs also activated the shedding of the endothelial protein C receptor from human umbilical vein endothelial cells. All these effects were inhibited by TMI-2. The present study shows that human plaque MPs carry catalytically active TACE/ADAM17 and significantly enhance the cell surface processing of the TACE/ADAM17 substrates TNF, TNFR-1, and endothelial protein C receptor, suggesting that TACE/ADAM17⁺ MPs could regulate the inflammatory balance in the culprit lesion.

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