Lipoprotein Associated Phospholipase A2 Inhibition Reduces Generation of Oxidized Fatty Acids

Abstract

Lipoprotein associated phospholipase A(2) (Lp-PLA(2)) is an emerging cardiovascular risk marker. After low-density lipoprotein (LDL) oxidation, Lp-PLA(2) generates oxidized nonesterified fatty acids and lysophosphatidylcholine, both of which have demonstrated proinflammatory and proapoptotic activities. Through the use of a selective inhibitor of Lp-PLA(2) (SB-677116), we investigated whether Lp-PLA(2) participates in the ex vivo generation of oxidized fatty acids (ox-FA). Due to the higher correlation between Lp-PLA(2) activity and small LDL particles, we investigated the effects of a selective Lp-PLA(2) inhibition on production of ox-FA in metabolic syndrome subjects with small LDL size <20.5 nm. Whole blood samples were incubated with vehicle (0 microM) or SB-677116 for 6 h at two different concentrations (0.3, 3.0 microM) to determine the effects of inhibitor on Lp-PLA(2) activity, the formation of oxidized esterified and nonesterified hydroxy-fatty acid (OH-FA) or ox-FA in 24 subjects. Whole blood incubation with Lp-PLA(2) inhibitor (0.3, 3.0 microM) reduced multiple C-18 OH-FA subclasses (p < 0.05 versus control). For the highly redox-sensitive 9-OH-FA, there was a concentration-dependent reduction in Lp-PLA(2) activity and 9-OH-FA (p (trend) = 0.0016) In conclusion, selective inhibition of Lp-PLA(2) reduced levels of OH-FA generated in whole blood of metabolic syndrome patients. These novel findings suggest that Lp-PLA(2) inhibition may attenuate some noxious downstream effects of lipid peroxidation that potentially include inflammatory responses.