Published online before print May 2, 2002, doi: 10.1161/01.RES.0000020017.84398.61
© 2002 American Heart Association, Inc.
Cellular Biology |
Platelet Phagocytosis and Processing of ß-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis
From the Division of Pharmacology (G.R.Y.D.M., D.M.M.D.C., D.M.J., W.M., A.G.H., H.B.), University of Antwerp, Antwerp, Belgium; the Department of Anatomical Pathology (S.C.), Electron Microscopy Unit, University of the Orange Free State, Bloemfontein, South Africa; HistoGeneX (M.W.M.K.), Edegem, Belgium; and the Department of Pathology (M.M.K.), General Hospital Middelheim, Antwerp, Belgium.
Correspondence to Guido R.Y. De Meyer, Division of Pharmacology, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerp, Belgium. E-mail gdemeyer{at}uia.ua.ac.be
Abstract— In human occluded saphenous vein grafts, we previously demonstrated cytotoxic foam cells, presumably derived from macrophages engulfing platelets. In the present study, we investigated whether platelet phagocytosis occurs in human atherosclerotic plaques, whether this activates macrophages, and whether the platelet constituent, amyloid precursor protein (APP), was involved. Immunohistochemistry documented the presence of APP, ß-amyloid peptide (Aß, cleaved from APP), and platelets (CD9), along with inducible NO synthase (iNOS) and cyclooxygenase-2, two markers of macrophage activation, around microvessels in advanced human carotid artery plaques (n=18). Aß colocalized with iNOS-expressing macrophages that were often surrounded by platelets. In vitro, murine J774 and human THP-1 macrophages were incubated with or without washed human platelets. Coincubation of macrophages and platelets led to platelet phagocytosis (electron and confocal microscopy) and formation of lipid-, APP-, and Aß-containing foam cells. These expressed iNOS mRNA (reverse transcription–polymerase chain reaction) and protein and produced nitrite and tumor necrosis factor-
(ELISA). Macrophage pretreatment with 4-(2-aminoethyl)benzenesulfonyl fluoride, a protease inhibitor, reduced APP processing and inhibited NO biosynthesis induced by platelet phagocytosis but not by lipopolysaccharides. Human atherosclerotic plaques and J774 and THP-1 macrophages contained mRNA of the APP-cleaving enzyme ß-secretase. This is the first demonstration of Aß, a peptide extensively studied in Alzheimer’s disease, in human atherosclerotic plaques. It was present in activated iNOS-expressing perivascular macrophages that had phagocytized platelets. In vitro studies indicate that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to Aß, resulting in iNOS induction. This represents a novel mechanism for macrophage activation in atherosclerosis.
Key Words: ß-amyloid peptide • amyloid precursor protein • foam cells • inducible nitric oxide synthase • nitric oxide
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