Phospholipases A2 (PLA2) are a family of
enzymes that catalyze the hydrolysis of the sn-2
ester bond of
glycerophospholipids liberating
lysophospholipids and
free fatty acids; important second messengers involved in
atherogenesis. Plasma
PAF-acetylhydrolase (PAF-AH) or
Lp-PLA2 is a Ca(2+)-independent PLA2 which is produced by monocyte-derived macrophages and by activated platelets, and circulates in plasma associated with
lipoproteins. PAF-AH catalyzes the removal of the acetyl/short acyl group at the sn-2 position of PAF and oxidized
phospholipids produced during
inflammation and oxidative stress. In humans, PAF-AH is mainly associated with small dense
LDL and to a lesser extent with HDL and with
lipoprotein(a). PAF-AH is N-glycosylated prior to secretion which diminishes its association with HDL raising the question of its distribution between the proatherogenic
LDL vs the antiatherogenic HDL. Hypercholesterolemic patients have higher plasma PAF-AH activity which is reduced upon hypolipidemic
therapy. PAF-AH specific inhibitor
darapladib stabilizes human and swine plaques, therefore challenging the antiatherogenic potential of PAF-AH shown in small animal models. Among secreted PLA2s (
sPLA2), the group X
sPLA2 (PLA2GX), due to its very high activity towards
phosphatidylcholine the main
phospholipid of
LDL, became an attractive target in
atherosclerosis. We showed that PLA2GX is present in human atherosclerotic lesions and that the PLA2GX-phospholipolysed
LDL triggers human macrophage-foam cell formation. In contrast to other
sPLA2s, including group IB, IIA and V, PLA2GX can efficiently hydrolyze PAF present in
lipoproteins or vesicles indicating that PLA2GX may be a novel player in PAF regulation upon inflammatory processes. By a genetic approach we uncovered a relatively rare polymorphism (Arg38Cys) which produces a catalytically inactive PLA2GX; although no association was observed with cardiovascular risk factors in the AtheroGene study, this result should be replicated in cohorts of other inflammatory diseases. We anticipate that mores studies will be necessary to sort out the exact role of extracellular PLA2 family members in
atherosclerosis initiation and progression.