LIPOPROTEINS ARE SUBSTRATES FOR HUMAN SECRETORY GROUP IIA PHOSPHOLIPASE A(2) - PREFERENTIAL HYDROLYSIS OF ACUTE-PHASE HDL

Group IIA secretory phospholipase A(2) is an acute phase enzyme, co-ex pressed with serum amyloid A protein, Both are present in atherosclero tic lesions. We report that human normal and acute phase high density lipoproteins and low density lipoprotein are effective substrates for human group IIA phospholipase A(2). The enzyme hydrolyzed choline and ethanolamine glycerophospholipids at the sn-2 position resulting in an accumulation of the corresponding lysophospholipids, including the un hydrolyzed alkyl and alkenyl ether derivatives. The hydrolysis of acut e phase high density lipoprotein was 2- to 3-fold more rapid and inten sive than of normal high density Lipoprotein. The hydrolysis of lipopr oteins was noted at enzyme concentration as low as 0.05 mu g/mg protei n, which was within the range observed in the circulation in acute and chronic inflammatory diseases. The enzyme hydrolyzed the different mo lecular species of the residual glycerophospholipids in proportion to their mass, showing no preference for the release of arachidonic acid. Group IIA phospholipase A(2) preferentially attacked the hydroxy and hydroperoxy linoleates and possibly other oxygenated fatty acids, whic h were released from the glycerophospholipids at early times of incuba tion. There was no effect on the content or molecular species composit ion of the sphingomyelins or neutral lipids of the lipoproteins.jlr In conclusion, human plasma lipoproteins are the first reported natural biological substrates for human group IIA phospholipase A(2). The enha nced hydrolysis of acute phase high density lipoproteins is probably d ue to its association with serum amyloid A protein, which enhances the activity of the enzyme and may promote its penetration to the lipid m onolayer, As sPLA(2)-induced hydrolysis of the lipoproteins leads to a ccumulation of lysophosphatidylcholine and potentially toxic oxygenate d fatty acids, overexpression of this enzyme may be proatherogenic.