scholarly journals Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor

1999 ◽  
Vol 338 (2) ◽  
pp. 479-487 ◽  
Author(s):  
Colin H. MACPHEE ◽  
Kitty E. MOORES ◽  
Helen F. BOYD ◽  
Dash DHANAK ◽  
Robert J. IFE ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Phospholipase A2 ◽  
Low Density Lipoprotein ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Biologically Active ◽  
Lipid Hydroperoxides ◽  
Low Density ◽  
Platelet Activating Factor Acetylhydrolase

A novel and potent azetidinone inhibitor of the lipoprotein-associated phospholipase A2 (Lp-PLA2), i.e. platelet-activating factor acetylhydrolase, is described for the first time. This inhibitor, SB-222657 (Ki = 40±3 nM, kobs/[I] = 6.6×105 M-1·s-1), is inactive against paraoxonase, is a poor inhibitor of lecithin:cholesterol acyltransferase and has been used to investigate the role of Lp-PLA2 in the oxidative modification of lipoproteins. Although pretreatment with SB-222657 did not affect the kinetics of low-density lipoprotein (LDL) oxidation by Cu2+ or an azo free-radical generator as determined by assay of lipid hydroperoxides (LOOHs), conjugated dienes and thiobarbituric acid-reacting substances, in both cases it inhibited the elevation in lysophosphatidylcholine content. Moreover, the significantly increased monocyte chemoattractant activity found in a non-esterified fatty acid fraction from LDL oxidized by Cu2+ was also prevented by pretreatment with SB-222657, with an IC50 value of 5.0±0.4 nM. The less potent diastereoisomer of SB-222657, SB-223777 (Ki = 6.3±0.5 µM, kobs/[I] = 1.6×104 M-1·s-1), was found to be significantly less active in both assays. Thus, in addition to generating lysophosphatidylcholine, a known biologically active lipid, these results demonstrate that Lp-PLA2 is capable of generating oxidized non-esterified fatty acid moieties that are also bioactive. These findings are consistent with our proposal that Lp-PLA2 has a predominantly pro-inflammatory role in atherogenesis. Finally, similar studies have demonstrated that a different situation exists during the oxidation of high-density lipoprotein, with enzyme(s) other than Lp-PLA2 apparently being responsible for generating lysophosphatidylcholine.

scholarly journals Platelet-activating factor acetylhydrolase and transacetylase activities in human plasma low-density lipoprotein

2001 ◽  
Vol 357 (2) ◽  
pp. 457 ◽  
Author(s):  
Demokritos C. TSOUKATOS ◽  
Theodoros A. LIAPIKOS ◽  
Alexandros D. TSELEPIS ◽  
M. John CHAPMAN ◽  
Ewa NINIO
Keyword(s):  
Human Plasma ◽  
Low Density Lipoprotein ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Platelet Activating Factor Acetylhydrolase

Platelet-activating factor formation during oxidative modification of low-density lipoprotein when PAF-acetylhydrolase has been inactivated

1994 ◽  
Vol 1212 (3) ◽  
pp. 353-360 ◽  
Author(s):  
Theodoros A. Liapikos ◽  
Smaragda Antonopoulou ◽  
Sonia-Athena P. Karabina ◽  
Demokritos C. Tsoukatos ◽  
Constantinos A. Demopoulos ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Low Density ◽  
Paf Acetylhydrolase

scholarly journals Detection of new epitopes formed upon oxidation of low-density lipoprotein, lipoprotein (a) and very-low-density lipoprotein. Use of an antiserum against 4-hydroxynonenal-modified low-density lipoprotein

1990 ◽  
Vol 265 (2) ◽  
pp. 605-608 ◽  
Author(s):  
G Jürgens ◽  
A Ashy ◽  
H Esterbauer
Keyword(s):  
Unsaturated Fatty Acids ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Lipid Hydroperoxides ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Dependent Manner ◽  
Lipoprotein A

4-Hydroxynonenal (HNE) is a major aldehydic propagation product formed during peroxidation of unsaturated fatty acids. The aldehyde was used to modify freshly prepared human low-density lipoprotein (LDL). A polyclonal antiserum was raised in the rabbit and absorbed with freshly prepared LDL. The antiserum did not react with human LDL, but reacted with CuCl2-oxidized LDL and in a dose-dependent manner with LDL, modified with 1, 2 and 3 mM-HNE, in the double-diffusion analysis. LDL treated with 4 mM of hexanal or hepta-2,4-dienal or 4-hydroxyhexenal or malonaldehyde (4 or 20 mM) did not react with the antiserum. However, LDL modified with 4 mM-4-hydroxyoctenal showed a very weak reaction. Lipoprotein (a) and very-low-density lipoprotein were revealed for the first time to undergo oxidative modification initiated by CuCl2. This was evidenced by the generation of lipid hydroperoxides and thiobarbituric acid-reactive substances, as well as by a marked increase in the electrophoretic mobility. After oxidation these two lipoproteins also reacted positively with the antiserum against HNE-modified LDL.

scholarly journals Platelet-Activating Factor Acetylhydrolase Is Mainly Associated With Electronegative Low-Density Lipoprotein Subfraction

Circulation ◽  
2003 ◽  
Vol 108 (1) ◽  
pp. 92-96 ◽  
Author(s):  
Sonia Benítez ◽  
José Luis Sánchez-Quesada ◽  
Vicent Ribas ◽  
Oscar Jorba ◽  
Francisco Blanco-Vaca ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Low Density ◽  
Platelet Activating Factor Acetylhydrolase ◽  
Lipoprotein Subfraction

scholarly journals Oxidation of low-density lipoprotein by hypochlorite causes aggregation that is mediated by modification of lysine residues rather than lipid oxidation

1994 ◽  
Vol 302 (1) ◽  
pp. 297-304 ◽  
Author(s):  
L J Hazell ◽  
J J M van den Berg ◽  
R Stocker
Keyword(s):  
Lipid Peroxidation ◽  
Lipid Oxidation ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Size Exclusion ◽  
Lipid Hydroperoxides ◽  
Low Density ◽  
Lysine Residues

Peroxidation of low-density lipoprotein (LDL) lipid is generally thought to represent the initial step in a series of modification reactions that ultimately transform the protein moiety of the lipoprotein into a form recognized by receptors different from those that bind native LDL. Uptake of LDL via these alternative receptors can lead to the formation of lipid-laden cells, which are typical for the early stages of atherogenesis. We have studied the oxidative modification of LDL by hypochlorite (-OCl), a powerful oxidant produced from H2O2 and chloride via the action of myeloperoxidase which is released from activated neutrophils and monocytes. Exposure of LDL to reagent or enzymically generated -OCl at 4 or 37 degrees C resulted in immediate and preferential oxidation of amino acid residues of apolipoprotein B-100, the single protein associated with LDL. Lysine residues quantitatively represented the major target and, like tryptophan, were oxidized to approximately the same extent with reagent or enzymically generated -OCl. In contrast, LDL lipid oxidation was less favoured than protein oxidation, as judged by the amounts of lipid hydroperoxides, chlorohydrins, cholesterol or fatty acid oxidation products formed. Treatment with -OCl caused aggregation of LDL, as shown by an increased turbidity of the oxidized LDL solution and elution from a size-exclusion h.p.l.c. column of high-molecular-mass LDL complexes. Chemical modification of lysine residues before oxidation with -OCl prevented aggregation, while it enhanced the extent of lipid peroxidation. Treatment of LDL with -OCl also caused the formation of carbonyl groups and release of ammonia; both these modifications were inhibited by lysine-residue modification before oxidation. These results demonstrate that aggregation reactions are dependent on initial lysine oxidation by -OCl, followed by deamination and carbonyl formation, but do not involve lipid (per)oxidation. We propose that the observed -OCl-mediated aggregation of LDL is caused, at least in part, by cross-linking of apoproteins by Schiff-base formation independently of lipid peroxidation.

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