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Originally published In Press as doi:10.1194/jlr.M300310-JLR200 on February 1, 2004

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Journal of Lipid Research, Vol. 45, 831-838, May 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Modification of LDL with human secretory phospholipase A2 or sphingomyelinase promotes its arachidonic acid-releasing propensity

Janne Oestvang*, Dominique Bonnefont-Rousselot{dagger}, Ewa Ninio§, Jukka K. Hakala**, Berit Johansen* and Marit W. Anthonsen1,{dagger}{dagger}

* Faculty of Natural Science and Technology, Norwegian University of Science and Technology, Trondheim, Norway
{dagger}{dagger} Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
{dagger} Laboratoire de Biochimie B, Groupe Hospitalier Pitié-Salpêtrière, and Institut Fédératif Coeur Muscle Vaisseaux, Paris, France
§ Institut National de la Santé et de la Recherche Médicale U525, Institut Fédératif Coeur Muscle Vaisseaux, and Université Pierre et Marie Curie, Paris, France
** Wihuri Research Institute, Helsinki, Finland

1 To whom correspondence should be addressed. e-mail: marit.w.anthonsen{at}medisin.ntnu.no

Oxidation and lipolytic remodeling of LDL are believed to stimulate LDL entrapment in the arterial wall, expanding the inflammatory response and promoting atherosclerosis. However, the cellular responses and molecular mechanisms underlying the atherogenic effects of lipolytically modified LDL are incompletely understood. Human THP-1 monocytes were prelabeled with [3H]arachidonic acid (AA) before incubation with LDL or LDL lipolytically modified by secretory PLA2 (sPLA2) or bacterial sphingomyelinase (SMase). LDL elicited rapid and dose-dependent extracellular release of AA in monocytes. Interestingly, LDL modified by sPLA2 or SMase displayed a marked increase in AA mobilization relative to native LDL, and this increase correlated with enhanced activity of cytosolic PLA2 (cPLA2) assayed in vitro as well as increased monocyte tumor necrosis factor-{alpha} secretion. The AA liberation was attenuated by inhibitors toward cPLA2 and sPLA2, indicating that both PLA2 enzymes participate in LDL-induced AA release.

In conclusion, these results demonstrate that LDL lipolytically modified by sPLA2 or SMase potentiates cellular AA release and cPLA2 activation in human monocytes. From our results, we suggest novel atherogenic properties for LDL modified by sPLA2 and SMase in AA release and signaling, which could contribute to the inflammatory gene expression observed in atherosclerosis.

Abbreviations: AA, arachidonic acid; BEL, bromoenol lactone; cPLA2, cytosolic phospholipase A2; iPLA2, Ca2+-independent phospholipase A2; LDLnat, native LDL; MAFP, methyl arachidonyl fluorophosphonate; MDA, malondialdehyde equivalents; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; OA, oleic acid; PLA2, phospholipase A2; SMase, sphingomyelinase; sPLA2, secretory phospholipase A2; TNF-{alpha}, tumor necrosis factor-{alpha}

Supplementary key words low density lipoprotein remodeling • inflammation • atherosclerosis • monocytes • oleic acid


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