Extracellular phospholipases in atherosclerosis.
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.
INSERM UMRS 937, Université Pierre et Marie Curie UPMC-Paris 6, Faculté de Médecine Pierre et Marie Curie, 91 Boulevard de l'Hôpital, Paris 75634 Cedex 13, France.
Sonia-Athina
SA
Karabina
Sarah
S
Gora
Rajai
R
Atout
Ewa
E
Ninio
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism
D008074:Lipoproteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase