Identification and analysis of products formed from phospholipids in the free radical oxidation of human low density lipoproteins

Milne, Ginger L.; Seal, Jennifer; Havrilla, Christine M.; Porter, Ned A.

doi:10.1194/jlr.m400311-jlr200

Cited by 33 publications

(24 citation statements)

References 47 publications

(56 reference statements)

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“…Hence, the oxidative modifications of plasma lipoproteins may be limited to a lesser extent; however, the oxidized LDL levels in plasma have been reported to correlate with the severity of cardiovascular diseases (39)(40)(41)(42). In addition, PCOOH has been identified as a major oxidized lipid in the early phase of LDL oxidation (33). In this context, our previous observations of higher plasma PCOOH concentrations in subjects with hyperlipidemia (8) and diabetes (10) prompted the hypothesis that PCOOH may initiate the atherosclerotic lesion formation by increasing monocyte adherence to the arterial wall because both hyperlipidemia and diabetes are strongly associated with an increased incidence of atherosclerosis (12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, PLPCOOH was used for all experiments as a representative of PCOOH molecular species unless otherwise stated because PLPCOOH is a predominant PCOOH molecule in human blood plasma (11,32) and is a major oxidized lipid molecule in the early phase of LDL oxidation (33). PAPCOOH was also used in some experiments because a series of secondary oxidation products derived from PAPC has been reported to possess various proatherogenic properties (15,16).…”

Section: Methodsmentioning

confidence: 99%

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Phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to intracellular adhesion molecule-1

Asai

Okajima

Nakagawa

et al. 2009

Journal of Lipid Research

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The accumulation of phosphatidylcholine hydroperoxide (PCOOH), a primary oxidation product of phosphatidylcholine (PC), in blood plasma and tissues has been observed in various pathological conditions, including atherosclerosis. However, the biological roles of PCOOH in these conditions remain unknown. To estimate the atherogenicity of PCOOH, we evaluated the effect of PCOOH on THP-1 monocytic cell adherence to immobilized vascular endothelial cell adhesion molecules. THP-1 cell adhesion to intracellular adhesion molecule-1 (ICAM-1) was dosedependently increased by addition of PCOOH. Phosphatidylcholine hydroxide (a hydroxyl analog of PCOOH) also induced THP-1 cell adhesion to ICAM-1, whereas nonoxidized PC, sn-2 truncated PCs, and other hydroperoxide compounds did not affect the adhesion. In the PCOOH-treated cells, obvious protruding F-actin-rich membrane structures were formed, and lymphocyte function-associated antigen-1 (LFA-1) was localized to the protruding structures. Cytochalasin D, an actin polymerization inhibitor, suppressed the PCOOH-induced cell adhesion to ICAM-1 and the membrane protrusions. These results indicate that PCOOH evokes LFA-1-mediated cell adhesion to ICAM-1 via actin cytoskeletal organization, and the mechanism may participate in monocyte adherence to the arterial wall in the initiation of atherosclerosis.-Asai, A., F. Okajima, K. Nakagawa, D. Ibusuki, K. Tanimura, Y. Nakajima, M. Nagao, M. Sudo, T. Harada, T. Miyazawa, and S. Oikawa. Phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to intracellular adhesion molecule-1. J. Lipid Res. 2009. 50: 957-965. Supplementary key words lipid oxidationOxidative lipid modifications play important roles in the pathogenesis of atherosclerosis (1-4). Among oxidatively modified lipids, phosphatidylcholine hydroperoxide (PCOOH), a primary oxidation product of phosphatidylcholine (PC), was observed to be accumulated in arterial walls and blood plasma in atherosclerotic rabbits (5). PCOOH was also identified in human atherosclerotic lesions (6, 7). Furthermore, PCOOH accumulation in plasma has been shown in human subjects with pathological conditions such as hyperlipidemia (8, 9), diabetes (10), uremia (9), and alcoholism (11). Because hyperlipidemia and diabetes are strongly associated with increased incidence of atherosclerosis (12-14), higher plasma PCOOH conditions in these patients may be involved in atherogenesis.In the course of phospholipid oxidation, PC is primarily oxidized to PCOOH. Further oxidative modification of PCOOH yields various secondary oxidation products. To date, a number of the secondary oxidation products have been reported to mediate several atherogenic processes (15, 16). For instance, a series of oxidized PCs with a truncated sn-2 acyl group (sn-2-truncated PCs), such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine, activate aortic endothelial cell binding to monocytes (17-19). The sn-2-truncated PCs with a terminal aldehyde gr...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to intracellular adhesion molecule-1

Asai

Okajima

Nakagawa

et al. 2009

Journal of Lipid Research

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“…In addition, it should be noted that we have previously undertaken studies to confirm the stability of EPA in the fish oil diet fed to rodents to ensure that the source of oxidized EPA products was not the diet and that they were generated in vivo (22). techniques have been developed to analyze intact phospholipids as well as oxidized phospholipids (23)(24)(25)(26)(27)(28). To provide direct evidence that these compounds exist esterified in phospholipids, we utilized UPLC/ESI-ion trap-MS 4 .…”

Section: Formation and Characterization Of A 3 /J 3 -Isops In Vitro-mentioning

confidence: 99%

Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A3/J3-Isoprostanes) in Vivo from Eicosapentaenoic Acid

Brooks

Milne

Yin

et al. 2008

Journal of Biological Chemistry

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Omega-3 (-3) polyunsaturated fatty acids (PUFAs) found in marine fish oils are known to suppress inflammation associated with a wide variety of diseases. Eicosapentaenoic acid (EPA) is one of the most abundant -3 fatty acids in fish oil, but the mechanism(s) by which EPA exerts its beneficial effects is unknown. Recent studies, however, have demonstrated that oxidized EPA, rather than native EPA, possesses anti-atherosclerotic, anti-inflammatory, and anti-proliferative effects. Very few studies to date have investigated which EPA oxidation products are responsible for this bioactivity. Our research group has previously reported that anti-inflammatory prostaglandin A 2 -like and prostaglandin J 2 -like compounds, termed A 2 /J 2 -isoprostanes (IsoPs), are produced in vivo by the free radical-catalyzed peroxidation of arachidonic acid and represent one of the major products resulting from the oxidation of this PUFA. Based on these observations, we questioned whether cyclopentenoneIsoP compounds are formed from the oxidation of EPA in vivo. Herein, we report the formation of cyclopentenone-IsoP molecules, termed A 3 /J 3 -IsoPs, formed in abundance in vitro and in vivo from EPA peroxidation. Chemical approaches coupled with gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) were used to structurally characterize these compounds as A 3 /J 3 -IsoPs. We found that levels of these molecules increase ϳ200-fold with oxidation of EPA in vitro from a basal level of 0.8 ؎ 0.4 ng/mg EPA to 196 ؎ 23 ng/mg EPA after 36 h. We also detected these compounds in significant amounts in fresh liver tissue from EPA-fed rats at basal levels of 19 ؎ 2 ng/g tissue. Amounts increased to 102 ؎ 15 ng/g tissue in vivo in settings of oxidative stress. These studies have, for the first time, definitively characterized novel, highly reactive A/J-ring IsoP compounds that form in abundance from the oxidation of EPA in vivo.

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“…Separation of lipid classes of LDL was achieved by modification of a method reported by Homan et al (30) using an aminopropyl HPLC column by Milne (31). A mixed solvent systems was used, which includes Solvent A: hexanes-THF (99:1); Solvent B: acetone-CH 2 Cl 2 (2:1); Solvent C: isopropyl alcohol/water (85:15).…”

Section: Identification Of a Novel Class Of Endoperoxidesmentioning

confidence: 99%

Identification of a Novel Class of Endoperoxides from Arachidonate Autoxidation

Yin

Morrow

Porter

2004

Journal of Biological Chemistry

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Free radical-initiated lipid autoxidation in low density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. Oxidation of the lipid components of LDL leads to a complex mixture of hydroperoxides, bicyclic endoperoxides, monocyclic peroxides, and serial cyclic peroxides. The oxidation compounds and/or their decomposition products can modify protein components, which may lead to various diseases. A novel class of peroxides (termed dioxolane-isoprostanes) having a bicyclic endoperoxide moiety characteristic of the isoprostanes and a dioxolane peroxide functionality in the same molecule was identified in the product mixture formed from in vitro autoxidation of cholesteryl arachidonate. The same products are also detected in in vitro oxidized LDL. Various mass spectrometric techniques have been applied to characterize these new peroxides. The structure of these compounds has also been confirmed by independent synthesis. We reason, based on the free radical mechanism of the transformation, that only the 12-and 8-peroxyl radicals (those leading to 12-HPETE and 8-HPETE) of arachidonate can form these new peroxides. We also suggest that the formation of these peroxides provides a rationale to explain the fact that 5-and 15-series isoprostanes are formed in preference to 8-and 12-series. Furthermore, series of other isoprostanes, such as dioxolane A 2 , D 2 , E 2 , etc., can be derived from the dioxolane-isoprostane peroxides. These findings offer further insights into the oxidation products of arachidonate and the opportunity to study their potential biological relevance.

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Identification and analysis of products formed from phospholipids in the free radical oxidation of human low density lipoproteins

Cited by 33 publications

References 47 publications

Phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to intracellular adhesion molecule-1

Phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to intracellular adhesion molecule-1

Formation of Highly Reactive Cyclopentenone Isoprostane Compounds (A3/J3-Isoprostanes) in Vivo from Eicosapentaenoic Acid

Identification of a Novel Class of Endoperoxides from Arachidonate Autoxidation

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