Riederer_2011_Atherosclerosis_214_338

OBJECTIVE: Previously we identified palmitoyl-lysophosphatidylcholine (LPC 16:0), as well as linoleoyl-, arachidonoyl- and oleoyl-LPC (LPC 18:2, 20:4 and 18:1) as the most prominent LPC species generated by the action of endothelial lipase (EL) on high-density lipoprotein (HDL). In the present study, the impact of EL and EL-generated LPC on interleukin-8 (IL-8) synthesis was examined in vitro in primary human aortic endothelial cells (HAEC) and in mice. METHODS AND RESULTS: Adenovirus-mediated overexpression of the catalytically active EL, but not its inactive mutant, increased endothelial synthesis of IL-8 mRNA and protein in a time- and HDL-concentration-dependent manner. While LPC 18:2 was inactive, LPC 16:0, 18:1 and 20:4 promoted IL-8 mRNA- and protein-synthesis, differing in potencies and kinetics. The effects of all tested LPC on IL-8 synthesis were completely abrogated by addition of BSA and chelation of intracellular Ca(2+). Underlying signaling pathways also included NFkB, p38-MAPK, ERK, PKC and PKA. In mice, adenovirus-mediated overexpression of EL caused an elevation in the plasma levels of MIP-2 (murine IL-8 analogue) accompanied by a markedly increased plasma LPC/PC ratio. Intravenously injected LPC also raised MIP-2 plasma concentration, however to a lesser extent than EL overexpression. CONCLUSION: Our results indicate that EL and EL-generated LPC, except of LPC 18:2, promote endothelial IL-8 synthesis, with different efficacy and kinetics, related to acyl-chain length and degree of saturation. Accordingly, due to its capacity to modulate the availability of the pro-inflammatory and pro-adhesive chemokine IL-8, EL should be considered an important player in the development of atherosclerosis.