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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1276.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Mildly Oxidized LDL Induces Expression of Group IIa Secretory Phospholipase A₂ in Human Monocyte–Derived Macrophages

Marit W. Anthonsen; Dominique Stengel; Delphine Hourton; Ewa Ninio; Berit Johansen

From the UNIGEN Center for Molecular Biology (M.W.A., B.J.), Norwegian University of Science and Technology, Trondheim, Norway; and Institut National de la Sante et de la Recherche Medicale (INSERM) Unit 321 (D.S., D.H., E.N.), Lipoproteines et Atherogenese, Hopital de la Pitie, Paris, France.

Correspondence to Berit Johansen, UNIGEN Center for Molecular Biology, Norwegian University of Science and Technology, N-7489 Trondheim, Norway. E-mail Berit.Johansen{at}chembio.ntnu.no

Abstract—Phospholipase A₂s (PLA₂s) constitute a family of enzymes that hydrolyze fatty acids of membrane phospholipids, thus initiating the synthesis of proinflammatory mediators. Various PLA₂s have been detected in human atherosclerotic arteries (advanced lesions); however, only the secretory group of PLA₂ has been shown to specifically hydrolyze low density lipoprotein (LDL)–associated phospholipids and, as such, may play a potential role in atherogenesis. In the present study, we investigated the expression pattern of group IIa, IV, and V PLA₂s in human macrophages, which are the key cells involved in the onset and perpetuation of atherosclerosis. Immunohistochemical staining by double labeling showed that the secretory nonpancreatic PLA₂ (snpPLA₂) is detectable in macrophages in the intima of early atherosclerotic lesions. Reverse transcription–polymerase chain reaction analysis of RNA extracted from human monocytes clearly showed that expression of group IV PLA₂ was enhanced during differentiation into macrophages, with an onset of induction at days 2 to 3 of differentiation. Group V snpPLA₂ was constitutively expressed on differentiation, whereas the detection of group IIa snpPLA₂ was dependent on both differentiation and subsequent stimulation of macrophages. Indeed, the transcription of group IIa snpPLA₂ in macrophages was induced by treatment with minimally modified or mildly oxidized LDL, whereas native, extensively oxidized, or acetylated LDL had no effect. To our knowledge, this is the first report describing induction of group IIa snpPLA₂ expression in human monocyte–derived macrophages. The mRNA levels of cytosolic PLA₂ group IV and snpPLA₂ group V remained unchanged on LDL treatment. Thus, our results show that the expression of distinct PLA₂ enzymes is regulated not only during differentiation of monocytes into macrophages but also on exposure of macrophages to distinct LDL species. Consequently, our results indicate a potential role for both cytosolic and secretory PLA₂ enzymes in inflammation and in macrophage functions related to atherosclerosis, with a specific role for group IIa snpPLA2 in LDL scavenging.

Key Words: atherosclerosis • phospholipase A₂ • LDL • immunohistochemistry • macrophages

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