[en] Recently, we showed that platelet phagocytosis occurs in human atherosclerotic plaques and leads to foam cell formation. Platelet phagocytosis, resulting in macrophage activation and iNOS induction, was associated with the formation of amyloid-beta peptide (Abeta) via proteolytic cleavage of platelet-derived amyloid precursor protein (APP), possibly by secretases. To test the involvement of gamma-secretase in this process, we used indomethacin, ibuprofen, and sulindac sulfide, non-steroidal anti-inflammatory drugs (NSAIDs) known to alter the gamma-secretase cleaving site of APP, on their ability to inhibit macrophage activation evoked by platelet phagocytosis. J774 macrophages were incubated with human platelets or lipopolysaccharide (LPS) with or without NSAIDs. Nitrite was quantified as a measure for inducible nitric oxide synthase (iNOS) activity. Indomethacin, ibuprofen, sulindac sulfide, and meloxicam concentration-dependently reduced nitrite production by macrophages incubated with platelets, but did not alter LPS-induced iNOS activity or platelet uptake. However, acetylsalicylic acid and naproxen, two NSAIDs without effect on the gamma-secretase cleaving site of APP, did not affect nitrite production in either platelet- or LPS-stimulated macrophages. Surface-enhanced laser desorption/ionization time-of-flight mass-spectrometry demonstrated time-dependent formation of Abeta-containing peptides after platelet phagocytosis, which could be inhibited by indomethacin. In conclusion, these results point to the involvement of gamma-secretase in macrophage activation following platelet phagocytosis.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Jans, Dominique ; Division of Pharmacology, University of Antwerp, Antwerp, Belgium
Martinet, Wim; Division of Pharmacology, University of Antwerp, Antwerp, Belgium
Fillet, Marianne ; Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Kockx, Mark M; Division of Pharmacology, University of Antwerp, Antwerp, Belgium
Merville, Marie-Paule ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Bult, Hidde; Division of Pharmacology, University of Antwerp, Antwerp, Belgium
Herman, Arnold G; Division of Pharmacology, University of Antwerp, Antwerp, Belgium
De Meyer, Guido R Y; Division of Pharmacology, University of Antwerp, Antwerp, Belgium
Language :
English
Title :
Effect of non-steroidal anti-inflammatory drugs on amyloid-beta formation and macrophage activation after platelet phagocytosis.
Publication date :
2004
Journal title :
Journal of Cardiovascular Pharmacology
ISSN :
0160-2446
eISSN :
1533-4023
Publisher :
Lippincott Williams & Wilkins, Hagerstown, United States - Maryland
Volume :
43
Issue :
3
Pages :
462-70
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique VWO
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