Published online before print November 24, 2003, doi: 10.1161/01.CIR.0000104564.01539.6A
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(Circulation. 2003;108:3128-3133.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Identification of 
-Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic Lesions
From the Department of Biochemistry and Molecular Biology (A.K.T., D.A.F.) and Pathology (J.M.), St Louis University Health Sciences Center, St Louis, Mo; Department of Medicine (F.-F.H.), Washington University, St Louis, Mo; and Departments of Cell Biology and Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention (M.-L.B., S.L.H.), Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to David A. Ford, PhD, Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, 1402 South Grand Blvd, St Louis, MO 63104. E-mail fordda{at}slu.edu
Received November 20, 2002; de novo received May 20, 2003; revision received August 18, 2003; accepted August 18, 2003.
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Abstract |
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Background— A role for myeloperoxidase (MPO) as a mediator of coronary artery disease and acute coronary syndromes has recently received considerable attention. Although active MPO and hypochlorite-modified proteins and peptides have been detected in human atherosclerotic lesions, detection of novel chlorinated oxidized lipid species with proatherogenic properties in vivo has not yet been reported. In this study we show that MPO-generated reactive chlorinating species promote selective oxidative cleavage of plasmalogens, liberating
-chloro fatty aldehydes and unsaturated lysophosphatidylcholine in human atherosclerotic lesions.
Methods and Results— Stable isotope dilution gas chromatography–mass spectrometry methods were used to identify and quantitate the -chloro fatty aldehyde, 2-chlorohexadecanal, in atherosclerotic versus normal human aorta. Compared with normal aorta, 2-chlorohexadecanal levels were elevated more than 1400-fold in atherosclerotic tissues. Parallel electrospray ionization mass spectrometry studies confirmed 34- and 20-fold increases in the plasmalogen cooxidation products, unsaturated lysophosphatidylcholine molecular species containing linoleic and arachidonic acid, respectively, within atherosclerotic compared with normal aorta. Unsaturated lysophosphatidylcholine containing docosahexaenoic acid was also detected in atherosclerotic but not in normal aorta. Exposure of primary human coronary artery endothelial cells to plasmalogen-derived lysophosphatidylcholine molecular species produced marked increases in P-selectin surface expression.
Conclusions— The present studies demonstrate that plasmalogens are attacked by MPO-derived reactive chlorinating species within human atheroma. The resultant species formed, -chloro fatty aldehydes and unsaturated lysophospholipids, possess proatherogenic properties, as shown by induction of P-selectin surface expression in primary human coronary artery endothelial cells.
Key Words: coronary disease • aorta • atherosclerosis
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Introduction |
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The initiation and progression of atherosclerosis is mediated, at least in part, by a complex set of pathways involving a local inflammatory reaction and lipoprotein oxidation at the site of the lesion.1–3 In the past decade, several studies have implicated myeloperoxidase (MPO)-catalyzed oxidation of target molecules as a biochemical mechanism that contributes to the pathophysiological sequelae of atherosclerosis. Specifically, active MPO has been purified from atheromatous tissue,4 and levels of MPO-specific products such as 3-chlorotyrosine5 and hypochlorite-modified proteins are elevated in atherosclerotic tissue compared with those in normal tissue.6,7 Additionally, blood MPO levels correlate with the incidence of coronary artery disease.8–10 Despite strong evidence of a role for MPO in human atherosclerosis, MPO is apparently not involved in murine atherosclerosis, because MPO is not present in murine atherosclerotic lesions and the MPO-knockout mouse develops atherosclerosis.11
Plasmalogens are a predominant membrane constituent in many cells of the cardiovascular system, and they contain a sn-1 vinyl ether bond.12–14 In vitro plasmalogen oxidation by MPO-derived reactive chlorinating species (RCS) results in the release of the -chloro fatty aldehyde species, 2-chlorohexadecanal (2-ClHDA) and 2-chlorooctadecanal (2-ClODA), from the sn-1 position with concomitant production of sn-1 lysophospholipids through a phospholipase-independent mechanism.15,16 Demonstration that MPO-catalyzed oxidation of plasmalogens in vivo with concomitant production of novel -chloro fatty aldehydes and sn-1 lysophosphatidylcholine (LPC) has not yet been reported. In the present study, we show that RCS formed in human atherosclerosis promotes oxidative cleavage of plasmalogens liberating novel lipids, -chloro fatty aldehydes, and unsaturated lysophosphatidylcholine that may serve as proatherogenic molecules.
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Methods |
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Materials
Atherosclerotic and normal aortic tissue was harvested from human postmortem autopsy specimens, rinsed, and submerged in PBS supplemented with 100 µmol/L diethylenetriaminepentaacetic acid and 100 µmol/L butylhydroxytoluene, frozen in liquid N2, and stored at -80°C until analysis. 2-Cl-[7,7,8,8-d4]-HDA (2-Cl-[d4]-HDA) was synthesized and purified as described previously.15 1-tetradecanoyl-2-hydroxy-sn-glycero-3-phosphocholine (14:0 lysophosphatidylcholine), 1,2-dioctadec-9',12'-enoyl-sn-glycero-3-phosphocholine (di-18:2 PC), and 1,2-dieicosatetra-5',8',11',14'-enoyl-sn-glycero-3-phosphocholine (di-20:4 PC) were purchased from Avanti. Pentafluorobenzyl hydroxylamine (PFB) was purchased from Aldrich Chemicals. P-selectin primary antibody was purchased from Santa Cruz. Horseradish peroxidase–conjugated rabbit anti-goat secondary antibody was purchased from Amersham.
Preparation of PFB Oximes of -Chloro Fatty Aldehydes and Quantitative Gas Chromatography-Mass Spectrometry Analysis
Lipid extracts isolated from the aortic tissue samples were prepared in the presence of internal standard, 2-Cl-[d4]-HDA, and tissue -chloro fatty aldehydes were converted to their respective PFB oxime derivatives before gas chromatography-mass spectrometry (GC-MS) analysis, as previously described.15 Quantification of 2-ClHDA was performed using selected ion monitoring (SIM) GC-MS as previously described.15 Specifically, the total integrated peak area arising from m/z 288, the structurally informative fragment ion produced by PFB-2-ClHDA, was compared with the total integrated peak area produced by m/z 292, the structurally informative fragment ion of PFB-2-Cl-[d4]-HDA. Values are normalized to total lipid phosphorous.
Electrospray Ionization Mass Spectrometric Analysis of Lysophosphatidylcholine Molecular Species
Electrospray ionization (ESI) tandem mass spectrometric analysis was conducted on a Finnigan TSQ 7000 mass spectrometer. The phospholipid extracts prepared in the presence of the internal standard, 14:0 lysophosphatidylcholine, were dissolved in chloroform/methanol (4/1, vol/vol) and methanolic LiCl or NaCl to enhance lithiated and sodiated ions. The solution was continuously infused into the ESI source with a Harvard syringe pump at a flow rate of 1 µL/min. The choline glycerophospholipids yield intense [M+Li]+ or [M+Na]+ adduct ions by electrospray ionization in the positive ion mode. Tandem mass spectrometry was performed by passage of the mass selected precursor ion from the first quadrupole into the collision cell (typically collision energies were 25 to 32 eV). Typically, spectra were averaged at 3 to 5 minutes and processed using ICIS software (Finnigan), and the mass of individual lysophosphatidylcholine molecular species were determined by comparisons to 14:0 lysophosphatidylcholine. Values are normalized to total lipid phosphorous.
Unsaturated Lysophosphatidylcholine Synthesis and HPLC Purification
Di-18:2 PC and di-20:4 PC were suspended in 100 mmol/L borate buffer pH 6.5 and diethyl ether (1/1, vol/vol) and converted to sn-1 lysophosphatidylcholine using Rhizopus lipase (9x104 U/mg substrate). The unsaturated lysophosphatidylcholine molecular species were purified by HPLC, and their purity was confirmed by thin-layer chromatography and by ESI-MS. Synthetic unsaturated lysophosphatidylcholine was immediately used for these studies before acyl migration to the sn-1 position, as ascertained by ESI-MS using collisionally induced dissociation. Quantification of purified unsaturated lysophosphatidylcholine molecular species was performed by GC-FID of their respective fatty acid methyl ester derivatives using arachidic acid (20:0 fatty acid) as an internal standard.14
P-Selectin Surface Expression Assay
A modified version of the method used by William et al17 was utilized. Human coronary artery endothelial cells, grown to confluence in 24-well plates, were incubated with indicated lipids in Hanks’ buffer for 5 minutes at 37°C in 95% O2/5% CO2. At the end of incubations, buffer was quickly removed and cells were immediately fixed with 1% paraformaldehyde overnight at 4°C. Cells were then washed 3 times with PBS and then blocked with Tris-buffered saline containing 0.1% Tween (vol/vol) supplemented with 0.8% BSA (wt/vol) and 0.5% fish gelatin (wt/vol) for 1 hour at 24°C. Primary goat polyclonal antibody (1:50) for P-selectin was used before treatments with horseradish peroxidase–conjugated rabbit anti-goat secondary antibody (1:5000). Subsequently, each well was incubated in the dark with the 3,3',5,5'-tetramethylbenzidine liquid substrate system. Reactions were stopped by the addition of sulfuric acid, and color development was measured with a microtiter plate spectrophotometer (Wallac) at 450 nm.
Peritonitis Model
Phagocytes were recruited to the peritoneum by injecting mice intraperitoneally with 1 mL of 4% thioglycollate broth. The resulting exudate (16 hours) was >70% neutrophil. Mice were then treated (16 hours after initial thioglycollate injection) with or without zymosan (250 µg/kg body weight, IP). Peritoneal lavage was performed 30 minutes later with PBS supplemented with 100 µmol/L butylhydroxytoluene and 100 µmol/L DTPA, snap frozen in liquid nitrogen, and stored at -80 until analysis.
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Results |
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Lipid extracts prepared from atherosclerotic human aorta samples were treated with PFB hydroxylamine, and the oxime derivatives of aldehyde products were subsequently analyzed by NICI GC-MS. Figure 1A shows the full scan mass spectrum of a derivative produced from a fatty aldehyde present in atherosclerotic aorta that had an identical retention time with that of authentic PFB oxime of 2-ClHDA (
8.4 minutes) and appears by fragmentation to be the PFB oxime of 2-ClHDA. Specifically, the structurally informative ion pair m/z 288/290 is present at a 3:1 ratio of abundances, indicating the molecule is monochlorinated because of the naturally occurring 3:1 isotopic abundance ratio of 35Cl and 37Cl. Additional structural confirmation that this molecule is the PFB oxime of 2-ClHDA is provided by the remaining ions in the acquired spectrum, which include the ion pair m/z 35/37 at a 3:1 ratio of abundance, along with m/z 414 (M-HF-Cl), 178, and 196, the latter 2 characteristic of PFB oxime derivatives.18 Additional analyses performed on lipids from both atherosclerotic and normal human aorta samples that were extracted in the presence of internal standard, 2-Cl-[d4]-HDA, were treated with PFB hydroxylamine and were analyzed by SIM-GC-MS for m/z 288 and m/z 292. The 2 peaks in Figure 1B show that SIM for m/z 288 of derivatives from atherosclerotic aorta correspond to the syn- and anti- isomers of the PFB oxime of 2-ClHDA18 with near identical retention times (8.3 and 8.4 minutes) as peaks corresponding to m/z 292 (from PFB-2-Cl-[d4]-HDA). In contrast, analysis of derivatives from normal aorta by SIM revealed the presence of only m/z 292 (the internal standard) with no detectable m/z 288 (Figure 1B). Figure 2 summarizes quantitative GC-MS analysis of 9 samples from human atherosclerotic lesions and 6 samples from normal human aorta. 2-ClHDA content in normal aorta was very low and only marginally detectable (Figure 2). The average 2-ClHDA content from atherosclerotic lesions was almost 1400 times that of normal aorta samples (2.08 versus 0.0015 pmol 2-ClHDA/nmol inorganic phosphate; Figure 2).
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Plasmalogens with 18 carbon sn-1 aliphatic groups are also targeted in atherosclerotic aorta. NICI GC-MS analyses of PFB oxime derivatives prepared from lipid extracts isolated from atherosclerotic human aorta revealed a mass fragmentation spectrum acquired for a peak at 9.05 minutes (the same retention time as that of the authentic PFB oxime of 2-ClODA) that contained structurally informative fragment ions (Figure 3A) that were 28 mass units greater than those of the structurally informative fragment ions produced from the PFB oxime of 2-ClHDA (eg, Figure 1A). As seen in Figure 3B, 2 peaks with the retention times of 8.95 and 9.05 minutes are detected using SIM of the structurally informative fragment ion of the PFB oxime of 2-ClODA, m/z 316, as well as SIM of m/z 35 in samples from human atherosclerotic aorta. In contrast, these ions were absent in normal aorta samples (Figure 3C). Collectively, these data demonstrate the oxidative targeting of 18 carbon vinyl ether aliphatic groups of plasmalogens in atherosclerotic aorta by MPO-generated RCS.
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Additional studies were performed to assess accumulation of the cooxidation product of RCS attack of plasmalogens, unsaturated lysophosphatidylcholine, in atherosclerotic lesions. Lipid extracts from both atherosclerotic and normal human aorta samples were analyzed by ESI-MS. Unsaturated lysophosphatidylcholine molecular species were detected in significantly higher levels in samples from atherosclerotic human aorta compared with normal aorta (Table). Octadec-9',12'-enoyl-sn-glycero-3-phosphocholine (18:2 lysophosphatidylcholine), eicosatetra-5',8',11',14'-enoyl-sn-glycero-3-phosphocholine (20:4 lysophosphatidylcholine), and docosahexa-4',7',10', 13',16',19'-enoyl-sn-glycero-3-phosphocholine (22:6 lysophosphatidylcholine) were elevated in atherosclerotic aorta compared with that detected in normal aorta. In conjunction with the detection of 2-ClHDA in atherosclerotic lesions, the presence of unsaturated molecular species of lysophosphatidylcholine in atherosclerotic aorta suggests that RCS-mediated plasmalogen degradation occurs in atherosclerosis. ESI-MS analysis of atherosclerotic aorta also demonstrated that the saturated lysophosphatidylcholine species hexadecanoyl-sn-glycero-3-phosphocholine (16:0 lysophosphatidylcholine) and stearoyl-sn-glycero-3-phosphocholine (18:0 lysophosphatidylcholine), both presumably produced by phospholipase A2, were present at elevated levels in atherosclerotic aorta compared with normal human aorta (Table). ESI-MS analysis in both the negative ion mode and positive ion mode of atherosclerotic tissue did not reveal the presence of lysophosphatidylethanolamine molecular species.
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In additional studies, phospholipids from normal human aorta were treated with HOCl, which led to the production of 2-ClHDA and sn-1 lyso 20:4 LPC (data not shown). However, pretreatment of phospholipids from normal human aorta with HCl fumes to eliminate plasmalogens demonstrated that the production of 2-ClHDA and sn-1 lyso 20:4 LPC by HOCl was dependent on the presence of plasmalogens in the lipid extract (data not shown). Additionally, data shown in Figure 4 demonstrate that activated phagocytes from wild-type mice produce 2-ClHDA, whereas this response is attenuated in activated phagocytes from the MPO-knockout mouse. Taken together, these data suggest that plasmenylcholine attack by RCS derived from MPO is the likely mechanism responsible for 2-ClHDA and unsaturated LPC accumulation in atherosclerosis.
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As a first step to determine the biological properties of unsaturated lysophosphatidylcholine molecular species, human coronary artery endothelial cells were treated with synthetic sn-1 (lyso) 18:2 lysophosphatidylcholine and 20:4 lysophosphatidylcholine at concentrations below their critical micellar concentrations, and P-selectin surface expression was assayed (Figure 5). As a positive control, 10 µmol/L platelet-activating factor induced highly increased P-selectin surface expression compared with control treatments. Remarkably, cells treated with either 10 µmol/L 18:2 lysophosphatidylcholine or 20:4 lysophosphatidylcholine resulted in significant increases in P-selectin surface expression. Additionally, analysis of lipid extracts from treated endothelial cells by ESI-MS using collisionally induced dissociation of molecular ions from lysophosphatidylcholine molecular species demonstrated that the unsaturated sn-1 lysophosphatidylcholine molecular species did not undergo acyl migration and was not significantly metabolized during these treatments. Taken together, these results demonstrate that a novel population of unsaturated lysophosphatidylcholine molecular species accumulates in atherosclerotic aorta through a mechanism that likely is dependent on MPO-derived RCS-mediated targeting of plasmalogens. The results also suggest a novel MPO-dependent mechanism that generates proatherogenic lipid mediators that can increase coronary artery endothelial cell surface expression of the leukocyte adhesion factor P-selectin.
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Discussion |
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Previous studies have suggested that MPO may participate in the pathophysiological sequelae of atherosclerosis.4,5,8–10,19–21 However, a link between MPO-generated RCS and formation of proatherogenic lipids at sites of human atheroma has not yet been established. The present studies provide the first evidence for MPO-mediated liberation of bioactive lipids in human atheroma via RCS. Furthermore, although in vivo studies have demonstrated the accumulation of 3-chlorotyrosine5 and HOCl-modified proteins in atherosclerotic lesions,6,7 the pathophysiological significance of these products remains unclear. In the studies herein, we have demonstrated that both
-chloro fatty aldehydes and unsaturated lysophosphatidylcholine, which are products derived from RCS attack of plasmenylcholine, are present in human atherosclerotic aorta (see scheme shown in Figure 6) and are potentially proatherogenic.
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The estimated molar 2-ClHDA content present in atherosclerotic lesions is 10 µmol/L (based on 2.08 pmol 2-ClHDA/nmol lipid phosphorous and 3400 nmol lipid phosphorous/g wet tissue and the assumptions that 75% of the wet weight is water and 2-ClHDA has equal access throughout this water). This amount of 2-ClHDA may act as a phagocyte chemoattractant, because chemoattraction has been previously been demonstrated for 2-ClHDA at both nanomolar and micromolar levels.15 Additional studies remain to determine the metabolic fate of 2-ClHDA, but it is likely that 2-ClHDA forms Schiff bases and may be oxidized to a fatty acids through the fatty alcohol-fatty acid cycle to undergo ß-fatty acid oxidation.
Saturated molecular species of lysophosphatidylcholine (including 16:0 lysophosphatidylcholine) produced by the action of phospholipase A2 on diacyl choline glycerophospholipids mediate several proatherogenic effects, including the induction of both coronary smooth muscle cell migration22 and monocyte chemotaxis.23 Lysophosphatidylcholine has also been suggested to be an important mediator of cardiovascular disease through its amphiphilic properties.24 The present findings not only have shown that saturated molecular species of lysophosphatidylcholine accumulate in atherosclerotic aorta but also show for the first time the presence of unsaturated lysophosphatidylcholine molecular species in atherosclerotic lesions that are likely produced by a phospholipase A2-independent mechanism (ie, RCS-mediated plasmalogen degradation, Figure 6). Another potential mechanism responsible for the production of unsaturated lysophosphatidylcholine molecular species is via the promiscuous endothelial lipase present in the vasculature as well as other phospholipases.25–27
Previous studies have demonstrated that the vinyl ether bond of plasmalogens has antioxidant properties by terminating the propagation of free radical reactions,28–31 therefore limiting lipid peroxidation. Furthermore, the localization of plasmalogens in the plasma membrane of cells of the cardiovascular system may act to shroud cells from reactive oxidizing species. In contrast, attack of plasmalogens by RCS likely reveals plasmalogens collectively as a molecular Trojan horse, because the masked vinyl ether bond is released as a reactive -chloro fatty aldehyde along with the concomitant production of an unsaturated lysophosphatidylcholine. Additionally, the present studies have revealed that unsaturated lysophosphatidylcholine, produced by RCS attack of plasmalogens, likely is an as-yet unrecognized proatherogenic molecule because it elicits increased surface expression of P-selectin on human coronary endothelial cells. Thus, in atherosclerotic tissue it is likely that plasmalogen attack by RCS produced by MPO represents a novel mechanism through which 2 potentially bioactive lipidic products are produced: -chloro fatty aldehydes and unsaturated lysophosphatidylcholine molecular species (Figure 6).
The present results show that both -chloro fatty aldehydes and unsaturated molecular species of lysophosphatidylcholine are produced in atherosclerotic, but not normal, aorta. The appearance of these RCS-derived molecules from plasmalogens is through a novel mechanism that may mediate at least in part the role of MPO in the pathophysiological sequelae of atherosclerosis. Thus, plasmalogens may represent previously unrecognized precursor molecules that potentially are converted to novel proatherogenic molecules.
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Acknowledgments |
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This research was supported jointly by NIH grants R01 HL 42665-11 (to Dr Ford), HL62526 (to Dr Hazen), HL70621 (to Dr Hazen), HL68588 (to Dr McHowat), and RR00954 (Washington University Mass Spectrometry Resource) as well as Grant-in-Aid 0151438Z (to Dr McHowat), Established Investigator Grant 0340042N (Dr Ford), and a predoctoral fellowship award (to A.K. Thukkani) from the American Heart Association. Support was also provided by the General Clinical Research Centers at the Cleveland Clinic Foundation (M01 RR018390) and by a Katzman Scholarship (A.K. Thukkani).
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