Modification of LDL with human secretory phospholipase A(2) or sphingomyelinase promotes its arachidonic acid-releasing propensity

摘要

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 Kith [H-3]arachidonic acid (AA) before incubation with LDL or LDL lipolytically modified bv secretory PIA, (sPLA(2)) or bacterial sphingomyelinase (SMase). LDL elicited rapid and dose-dependent extracellular release of AA in monocytes. Interestingly, LDL modified by sPLA, or SMase displayed a marked increase in AA mobilization relative to native LDL, and this increase correlated with enhanced activity of cytosolic PLA(2) (cPLA(2)) assaved in vitro as well as increased monocyte tumor necrosis factor-alpha secretion. The AA liberation was attenuated by inhibitors toward cPLA(2) and sPLA(2), indicating that both PIA, enzymes participate in LDL-induced AA release.jlr In conclusion, these results demonstrate that LDL lipolytically modified by sPLA(2) or SMase potentiates cellular AA release and cPLA(2) activation in human monocytes. From our results, we suggest novel atherogenic properties for LDL modified by sPLA(2) and SMase in AA release and signaling, 0 which could contribute to the inflammatory gene expression observed in atherosclerosis-Oestvang, J., D. Bonne-font-Rousselot, E. Ninio, J. K. Hakala, B. Johansen, and M. W. Anthonsen. Modification of LDL with human secretory phospholipase A2 or sphingomyetinase promotes its arachidonic acid-releasing propensity. J. Lipid Res. 2004. 45: 831-838.