E. Ozhegov, Yonis Ahmed, Xiao‐Ping Li
Mar 1, 2008
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The FASEB Journal
Abstract
1‐palmitoyl 2‐oxovaleroyl phosphatidyl choline (POVPC) is one of the major products of phospholipid (PL) oxidation generated in atherosclerotic lesions and other sites of chronic inflammation. The aim of the present study was to examine how metabolism of POVPC by macrophages affects its pro‐inflammatory potential. Using ESI/MS analysis we found that POVPC was rapidly metabolized in the THP‐1 derived macrophages (THP‐1DM) via 2 major pathways: hydrolysis to 1‐palmitoyl‐2‐lysophosphatidylcholine (lyso‐PC) and reduction to 1‐palmitoyl‐2‐hydroxyvaleroyl phosphatidylcholine (PHVPC). When the THP‐1DM were incubated with PHVPC only the hydrolysis product lyso‐PC was detected. Inhibition of phospholipase A2 (PLA2) by Pefabloc led to a significant increase in the reduction of POVPC to PHVPC and diminished the rate of PHVPC metabolism. As determined by qRT‐PCR exposure to POVPC resulted in time‐ and concentration‐dependent increase in TNFα, IL‐8, IL‐1β, IL‐6 and MCP‐1 mRNA. PHVPC was 3–8 fold more potent than POVPC, whereas lyso‐PC was as active as POVPC. Pefabloc increased cytokine induction by POVPC and PHVPC consistent with increased accumulation of PHVPC upon inhibition of PLA2‐mediated hydrolysis. Treatment with POVPC decreased the expression of CD‐36 and SRA. Decrease in the scavenger receptor expression was accompanied by a decrease in lipid accumulation as measured by oil red O staining. PHVPC was more potent in suppressing scavenger receptor expression and preventing lipid uptake than POVPC. We suggest that reductive metabolism could enhance the inflammatory effects of PL aldehydes and that PLA2, by preventing reduction of oxidized PL, might have a protective role against inflammation and atherosclerotic lesion formation. Funded by NIH grants HL65618, ES11860 and HL55477.