title: Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein.
abstract: Our group has previously demonstrated that oxidized phospholipids in mildly oxidized LDL (MM-LDL) produced by oxidation with lipoxygenase, iron, or cocultures of artery wall cells increase monocyte-endothelial interactions and this sequence of events is blocked by HDL. To obtain further insight into the mechanism by which HDL abolishes the activity of MM-LDL we investigated the effect of the HDL-associated ester hydrolase paraoxonase (PON). Treatment of MM-LDL with purified PON significantly reduced the ability of MM-LDL to induce monocyte-endothelial interactions. Inactivation of PON by pretreating HDL with heat or EDTA reduced the ability of HDL to inhibit LDL modification. HPLC analysis of phospholipids isolated from MM-LDL before and after treatment with purified PON showed that the 270 nm absorbance of phospholipids was decreased, while no effect was observed on 235 nm absorbance. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and specific fractions of Ox-PAPC isolated by HPLC induced the same monocyte-endothelial interactions as did MM-LDL. Biologically active and inactive HPLC fractions of Ox-PAPC were compared by fast atom bombardment-mass spectrometry which revealed that active fractions possessed ions with a mass to charge [correction of change] ratio greater than native PAPC by multiples of 16 D suggesting the addition of 3 and 4 oxygen atoms to PAPC. Comparison of Ox-PAPC by fast atom bombardment-mass spectrometry before and after PON treatment showed that PON destroyed these multi-oxygenated molecules found in biologically active fractions of Ox-PAPC. These results suggest that PON in HDL may protect against the induction of inflammatory responses in artery wall cells by destroying biologically active lipids in mildly oxidized LDL.
authors.affiliation: Department of Pathology, University of California, Los Angeles 90095-1732, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Watson
authors.forename: J A
authors.initials: JA
authors.lastname: Berliner
authors.forename: S Y
authors.initials: SY
authors.lastname: Hama
authors.forename: B N
authors.initials: BN
authors.lastname: La Du
authors.forename: K F
authors.initials: KF
authors.lastname: Faull
authors.forename: A M
authors.initials: AM
authors.lastname: Fogelman
authors.forename: M
authors.initials: M
authors.lastname: Navab
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D001011:Aorta; D043303:Aryldialkylphosphatase; D002478:Cells, Cultured; D018920:Coculture Techniques; D004492:Edetic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D004950:Esterases / Q000097:blood* / Q000302:isolation & purification; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood* / Q000302:isolation & purification; D008077:Lipoproteins, LDL / Q000097:blood* / Q000302:isolation & purification / Q000494:pharmacology*; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000378:metabolism; D010743:Phospholipids / Q000302:isolation & purification / Q000378:metabolism; D011817:Rabbits; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010743:Phospholipids; D004492:Edetic Acid; D004950:Esterases; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D043303:Aryldialkylphosphatase