Journal of Lipid Research (May 2004)
Modification of LDL with human secretory phospholipase A2 or sphingomyelinase promotes its arachidonic acid-releasing propensity
Abstract
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-α 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.