Apolipoprotein A-I Promotes the Formation of Phosphatidylcholine Core Aldehydes That Are Hydrolyzed by Paraoxonase (PON-1) during High Density Lipoprotein Oxidation with a Peroxynitrite Donor

High density lipoprotein (HDL) is rich in polyunsaturated phospholipids that are sensitive to oxidation. However, the effect of apolipoprotein A-I and paraoxonase-1 (PON-1) on phosphatidylcholine oxidation products has not been identified. We subjected native HDL, trypsinized HDL, and HDL lipid suspensions to oxidation by the peroxynitrite donor, 3-morpholinosydnonimine. HDL had a basal level of phosphatidylcholine mono- and di-hydroperoxides that increased to a greater extent in HDL, compared with either trypsinized HDL or HDL lipid alone. Phosphatidylcholine core aldehydes, which were present in small amounts, increased 10-fold during oxidation of native HDL, compared with trypsinized HDL (p = 0.004), and 4-fold compared with HDL lipid suspensions (p = 0.0021). In addition, the content of lysophosphatidylcholine increased 300% during oxidation of native HDL, but only 80 and 25%, respectively, during oxidation of trypsinized HDL and HDL lipid suspensions. Phosphatidylcholine isoprostanes accumulated in comparable amounts during the oxidation of all three preparations. Incubation of apolipoprotein A-I with 1-palmitoyl-2-linoleoyl glycerophosphocholine proteoliposomes in the presence of 3-morpholinosydnonimine or apoAI with phosphatidylcholine hydroperoxides resulted in a significant increase in phosphatidylcholine core aldehydes with no formation of lysophosphatidylcholine. We propose that apolipoprotein A-I catalyzes a one-electron oxidation of alkoxyl radicals. Purified PON-1 hydrolyzed phosphatidylcholine core aldehydes to lysophosphatidylcholine. We conclude that, upon HDL oxidation with peroxynitrite, apolipoprotein AI increases the formation of phosphatidylcholine core aldehydes that are subsequently hydrolyzed by PON1. High density lipoprotein (HDL) is rich in polyunsaturated phospholipids that are sensitive to oxidation. However, the effect of apolipoprotein A-I and paraoxonase-1 (PON-1) on phosphatidylcholine oxidation products has not been identified. We subjected native HDL, trypsinized HDL, and HDL lipid suspensions to oxidation by the peroxynitrite donor, 3-morpholinosydnonimine. HDL had a basal level of phosphatidylcholine mono- and di-hydroperoxides that increased to a greater extent in HDL, compared with either trypsinized HDL or HDL lipid alone. Phosphatidylcholine core aldehydes, which were present in small amounts, increased 10-fold during oxidation of native HDL, compared with trypsinized HDL (p = 0.004), and 4-fold compared with HDL lipid suspensions (p = 0.0021). In addition, the content of lysophosphatidylcholine increased 300% during oxidation of native HDL, but only 80 and 25%, respectively, during oxidation of trypsinized HDL and HDL lipid suspensions. Phosphatidylcholine isoprostanes accumulated in comparable amounts during the oxidation of all three preparations. Incubation of apolipoprotein A-I with 1-palmitoyl-2-linoleoyl glycerophosphocholine proteoliposomes in the presence of 3-morpholinosydnonimine or apoAI with phosphatidylcholine hydroperoxides resulted in a significant increase in phosphatidylcholine core aldehydes with no formation of lysophosphatidylcholine. We propose that apolipoprotein A-I catalyzes a one-electron oxidation of alkoxyl radicals. Purified PON-1 hydrolyzed phosphatidylcholine core aldehydes to lysophosphatidylcholine. We conclude that, upon HDL oxidation with peroxynitrite, apolipoprotein AI increases the formation of phosphatidylcholine core aldehydes that are subsequently hydrolyzed by PON1. low density lipoproteins apolipoprotein dimyristoyl glycerophosphocholine N-bis(carboxymethylamino)-ethylglycinepentaacetic acid) heptafluorobutyric acid high density lipoproteins liquid chromatography/electrospray ionization/mass spectrometry platelet-activating factor-acetylhydrolase palmitoyl-linoleoyl glycerophosphocholine paraoxonase-1 3-morpholinosydnonimine polyacrylamide gel electrophoresis phosphate-buffered saline butylated hydroxytoluene high pressure liquid chromatography 1-palmitoyl-2-(5-oxo)valeroyl-sn-glycero-3-phosphocholine 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine 1-palmitoyl-2-(9-oxo)nonanoyl-sn-glycero-3-phosphocholine 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine 1-palmitoyl-2-arachidonoyl glycero-3-phosphocholine There is significant evidence that the role of lipoproteins in cardiovascular disease involves oxidation of the lipid-protein complex (1Chisolm G.M. 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Biol. 1997; 17: 786-796Crossref PubMed Scopus (162) Google Scholar) have shown that there is a marked gradient of the tocopherol and carotenoid classes of lipid-soluble antioxidants among the major lipoproteins. Very low density lipoproteins, LDL, and HDL were shown to have an average of 43, 10, and 0.7 antioxidant molecules per particle, respectively. On this basis alone, one would predict that HDL would be the lipoprotein complex most susceptible to oxidation. Indeed, HDL is as susceptible or more susceptible to oxidation in vitro than is LDL (7Francis G.A. Biochim. Biophys. Acta. 2000; 1483: 217-235Crossref PubMed Scopus (110) Google Scholar). However, HDL has been shown to protect LDL from oxidation in vitro (10Mackness M.I. Durrington P.N. Mackness B. Curr. Opin. Lipidol. 2000; 11: 383-388Crossref PubMed Scopus (172) Google Scholar). The factors protecting against formation of lipid hydroperoxides in plasma appear to be apoA-I (11Garner B. Witting P.K. Waldeck A.R. 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Moncada S. Biochem. J. 1992; 281: 419-424Crossref PubMed Scopus (622) Google Scholar). Therefore, it mimics the environment that lipoproteins may be exposed to in the vasculature (15Beckman J.S. Beckman T.W. Chen J. Marshall P.A. Freeman B.A. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 1620-1624Crossref PubMed Scopus (6731) Google Scholar). We have compared the oxidation products of native HDL, trypsinized HDL, and HDL lipid suspensions and phosphatidylcholine apoA-I proteoliposomes. Our results show that apoA-I increases the formation of phosphatidylcholine core aldehydes. In addition, we observed that lysophosphatidylcholine was formed in significant amounts only during oxidation of intact HDL, consistent with activation of a phospholipase A2-like activity. We conclude that PON-1 has a phospholipase A2-like activity toward phosphatidylcholine core aldehydes. SIN-1,N-bis(carboxymethylamino)-ethylglycinepentaacetic acid) (DTPA), dipentadecanoylglycerophosphocholine, 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine (PLPC), 1-palmitoyl-2-arachidonoylglycero-3-phosphocholine (PAPC), and dimyristoyl-sn-glycero-3-phosphocholine (DMPC) were from Avanti Inc. (Alabaster, AL); t-butyl-hydroperoxide and trypsin (bovine pancreas) were purchased from Sigma. Polyclonal rabbit anti-human apoA-I and anti-human apoA-II antibodies were prepared in the laboratory (24Connelly P.W. Vezina C. Maguire G.F. Methods Enzymol. 1996; 263: 188-208Crossref PubMed Google Scholar), and anti-rabbit IgG alkaline phosphatase conjugate was purchased from Bio-Rad. 1-Palmitoyl-2-(5-oxo)valeroyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-(9-oxo)nonanoyl-sn-glycero-3-phosphocholine and the corresponding core acids were prepared in the laboratory by reductive ozonization of PLPC and PAPC, as described previously (25Ravandi A. Kuksis A. J. Biochem. Biophys. 1995; PubMed Scopus Google Scholar). phospholipids were the from used in liquid spectrometry were and were of and were by HDL was from of by and J. Clin. Invest. PubMed Scopus Google Scholar), and in phosphate-buffered saline HDL S.M. Biochem. 87: PubMed Scopus Google Scholar) was by the peroxynitrite donor, to in the presence of a R. Beckman J.S. Freeman B.A. Biochem. Biophys. PubMed Scopus Google Scholar). an was the oxidation was by the of butylated hydroxytoluene and HDL lipid-soluble oxidation products were with Biochem. PubMed Scopus Google Scholar). The of the oxidation products were as of phosphatidylcholine was in the presence of an polyacrylamide gel PubMed Scopus Google Scholar). proteins were either or to and rabbit anti-human apoA-I or anti-human apoA-II HDL oxidation products were as described of an The phase was and were in of was a phase in a liquid to a with a The was with a gradient of by to by by a of A. Kuksis A. H. FEBS Lett. 1996; PubMed Scopus Google Scholar). The was in the The phosphatidylcholine was The was with were in the The in the are The of the are The of the oxidation products were on the by the of the fatty acid of the and the of the phosphatidylcholine was in and to HDL an enzyme to HDL of The was HDL was to and subjected to oxidation with of the oxidation was and the was by the of by of the HDL HDL was with and the was the was and the lipid was This to as HDL lipid was with to conditions to used HDL oxidation. oxidation products were with and of the were prepared HDL was from from by and and in was by an a of a gradient of to glycerophosphocholine hydroperoxides were prepared by of PLPC with t-butyl-hydroperoxide which the was by of to a of Biochem. 1998; PubMed Scopus Google Scholar). in PLPC hydroperoxides were prepared with PLPC in the of Biochem. Biophys. Res. PubMed Scopus Google Scholar), and were to in the presence of to be used oxidation were prepared by of of in a J.S. M.W. C. M.J. J. Lipid Res. 1996; 37: Full Text PDF PubMed Google Scholar). was also exposed to and used the as described were with to in the presence of a of of were also prepared and by all an was the oxidation was by the of and lipid-soluble oxidation products were with The lipid was and in of were prepared by J. Lipid Res. Full Text PDF PubMed Google Scholar). apoA-I in was to a lipid of 1-palmitoyl-2-(5-oxo)valeroyl-sn-glycero-3-phosphocholine and the corresponding and or 1-palmitoyl-2-(9-oxo)nonanoyl-sn-glycero-3-phosphocholine and the corresponding acid and with and in The were against PON-1 was from plasma chromatography and chromatography of as described A. La Du B.N. 19: Google La Du B.N. 1995; Google Scholar). of PON-1 one corresponding to In to other such as or we the PON-1 by pressure liquid chromatography in liquid with The was to The was with a gradient of to in by a of the of PON-1 was by the of of PON-1 in was by trypsin with of trypsin The were on a phase to a The was as described by Biochem. 1998; 263: PubMed Scopus Google Scholar), and the were by a gradient from to in of and and of acid and The the of the was to by the and of a The as the gradient The was a by three of the three most was used to of that a were the against the high was compared with the corresponding to the was was PON-1 was as the and the product was in were used to the of PON-1 activity was as described La Du B.N. J. Google Scholar). results are as among were of in were used of HDL, HDL, and HDL are shown in of HDL phosphatidylcholine as the major with amounts of and which are in of of the the phosphatidylcholine from HDL that the major were and was the which are in the a with the phosphatidylcholine was the lysophosphatidylcholine was were with corresponding to phosphatidylcholine and core aldehydes. The the lysophosphatidylcholine the presence of the and as major in both native and HDL. In contrast to HDL, phosphatidylcholine in the HDL lipid suspensions was by as from the of phosphatidylcholine core aldehydes, and lysophosphatidylcholine. The of the major from to of a HDL of oxidation with is shown in The major and glycerophosphocholine The major of a of HDL and are shown in B. The and the of core aldehydes of There was also a small the core The major mono- and present a of HDL with are shown in The the and and the and The from the phase the of the of the fatty The major of phosphatidylcholine present a of HDL with are shown in the and to the and the and to the and The to an The isoprostanes as consistent with a of The were as The the major core aldehydes of phosphatidylcholine that were present a of HDL with are shown in The and to the and and and to the and The and were to the and the respectively. The aldehydes are as in of The of the hydroperoxides of phosphatidylcholine was most and the level during oxidation of native HDL, compared with HDL lipid suspensions or trypsinized HDL (p In the of the was more native and trypsinized HDL and HDL lipid the of was the native HDL (p The of core aldehydes that of hydroperoxides and was native HDL than trypsinized HDL or HDL lipid suspensions. The of the lysophosphatidylcholine was native HDL (p compared with HDL lipid suspensions or trypsinized HDL. proteoliposomes were with to and the formation of core aldehydes was There was a greater increase in PLPC hydroperoxides in the presence of apoA-I to the of core aldehydes compared with (p The evidence that apoA-I the formation of core aldehydes. However, to the that phosphatidylcholine oxidation products and may have the we studied the formation of core aldehydes in the of by phosphatidylcholine The effect of apoA-I on the of phosphatidylcholine hydroperoxides core aldehydes is shown in Phosphatidylcholine hydroperoxides a in the presence of compared with in the of apoA-I There was a of core aldehydes in the presence of compared with the of apoA-I proteoliposomes were prepared with and either a of and or a of and PON-1 and proteoliposomes to (p and and also and proteoliposomes to (p and The of was greater than the of and were hydrolyzed to a was not consistent with PON-1 or fatty but not the intact fatty acids in the of This is also consistent with the of the of mono- or in the not The of the core aldehydes and acids by PON-1 in this that the high of lysophosphatidylcholine during HDL oxidation by be by The apoproteins of native and HDL were by and that apoA-I was the major all with the of the apoA-I apoA-I and were by The of was by with antibodies and antibodies not HDL PON-1 activity was conditions PON-1 activity of HDL to of the a of the of and to of the this level to the of activity was to peroxynitrite or lipid oxidation the activity of native HDL was during with HDL lipid suspensions that had been by with This resulted in a significant in it was not as as that observed by oxidation of HDL. This that both peroxynitrite and lipid oxidation products are the in activity. the of PON-1 activity during oxidation of HDL with this activity was a of during the oxidation of apoA-I proteoliposomes with and compared with its activity with or the oxidation or PON-1 activity was by compared with (p with PLPC exposed to In PON-1 was with and or and there was of PON-1 activity and compared with This that PON-1 activity is not by aldehydes. Incubation of PON-1 with PON-1 activity by the marked of activity of PON-1 that we observed during oxidation of HDL was to the of lipid oxidation products and This that peroxynitrite is of HDL to a of the content and of which is modified by the presence of apoA-I and The major phosphatidylcholine oxidation products were the mono- and core aldehydes, and The high of the phosphatidylcholine core aldehydes during peroxynitrite oxidation of native HDL, in the presence of is of this the of such as H. Kuksis A. J. 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PON-1 activity is during HDL it that its phospholipase A2-like activity toward core aldehydes is We the phosphatidylcholine isoprostanes of the and a of The of products that formation is by the of peroxynitrite and acid with or no to the proteins of HDL. the present has shown that apoA-I increases the of a of the core aldehydes, that have been as a major of modified LDL N. H. C. Fogelman A.M. Arterioscler. Thromb. Vasc. Biol. 2000; PubMed Scopus Google Scholar). We propose that, in this of apoA-I is with the activity of and PON-1 to phosphatidylcholine hydroperoxides to biologically However, in the of a response, apoA-I would its the activity of both and PON-1 would This of HDL would be consistent with the and of Lenten Lenten B.J. Hama S.Y. de Beer F.C. Stafforini D.M. McIntyre T.M. Prescott S.M. La Du B.N. Fogelman A.M. Navab M. J. Clin. Invest. 1995; 96: 2758-2767Crossref PubMed Scopus (709) Google Scholar) that HDL can be from an anti-inflammatory lipoprotein to a lipoprotein W. Memon R.A. Feingold K.R. Grunfeld C. J. Infect. Dis. 2000; 181 Suppl. 3: S462-S472Crossref PubMed Scopus (333) Google Scholar). In the present results show that peroxynitrite oxidation of HDL phosphatidylcholine results in a of oxidation However, the of the of and are by apoA-I and The of the core aldehydes, which are by of the fatty are as are by the phospholipase A2-like activity of the HDL.

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