Published online before print April 6, 2006, doi: 10.1161/01.ATV.0000221231.56617.67
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Secretory Phospholipase A2 Group V
Lesion Distribution, Activation by Arterial Proteoglycans, and Induction in Aorta by a Western Diet
From AstraZeneca (B.R., M.U., A.-C.J.-R., C.H., P.C., E.H.-C.), R&D, Molecular Pharmacology, Mölndal, Sweden; and Wallenberg Laboratory (H.P., L.M.-H., M.R.-L., E.H.-C.), Sahlgrenska University Hospital, Göteborg, Sweden.
Correspondence to Eva Hurt-Camejo, AstraZeneca, R&D, Molecular Pharmacology, Mölndal S-431 83, Sweden. E-mail eva.hurt-camejo{at}astrazeneca.com
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Abstract |
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Objective— To study the distribution of group V secretory phospholipase A2 (sPLA2) in human and mouse lesions and compare its expression by human vascular cells, its activity toward lipoproteins, and the interaction with arterial proteoglycans (proteoglycans) with those of sPLA2-IIA. In addition, we also investigated the effect of a Western diet and lipopolysaccharide challenge on the aortic expression of these enzymes in mouse models.
Methods and Results— Immunohistochemistry showed sPLA2-V in human and mouse lesions to be associated with smooth muscle cells and also surrounding foam cells in lipid core areas. mRNA of the enzyme was expressed in human lesions and human vascular cells, supporting the immunohistochemistry data. sPLA2-V but not sPLA2-IIA was active on lipoproteins in human serum. The association with proteoglycans enhanced 2- to 3-fold sPLA2-V activity toward low-density lipoproteins but not that of the group IIA enzyme. Experiments in mouse models showed that treatment with a Western diet induced expression of sPLA2-V but not that of sPLA2-IIA in aorta. On the other hand, lipopolysaccharide-induced acute inflammation augmented the expression of sPLA2-IIA but not that of sPLA2-V.
Conclusions— These results indicate that these phospholipases could have different roles in atherosclerosis.
SPLA2-V was observed in human and mouse lesions associated with smooth muscle cells and surrounding foam cells in lipid cores. Proteoglycans increased the activity of sPLA2-V toward low-density lipoproteins. Western diet induced sPLA2-V expression in mouse aorta but not that of sPLA2-IIA. These enzymes may contribute to atherosclerosis by different pathways.
Key Words: phospholipase • atherogenesis • inflammation • lipoprotein-retention • proteoglycans
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Introduction |
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During atherosclerosis development, there is a progressive decrease of the lesion phospholipid content and enrichment in cholesterol.1 Furthermore, apolipoprotein B (apoB) lipoproteins isolated from human and rabbit lesions contain less phosphatidylcholine (PC) and more sphingomyelin than circulating lipoproteins.2,3 Therefore, lipoproteins trapped in the intima appear to be hydrolyzed by secretory phospholipases.4 These enzymes may contribute to atherosclerosis by hydrolysis of low-density lipoprotein (LDL) phospholipids that induce fusion and increase binding of cholesterol-rich particles to intima proteoglycans, triggering further modifications.5–8 In addition, phospholipase(s) A2 contribute to local release of lyso-phospholipids and nonesterified fatty acids, which have proinflammatory properties in arterial cells.9–12
See page 1421
Secretory phospholipase A2 (sPLA2) group IIA is present in human atherosclerotic lesions, and experimental and clinical evidence suggest its involvement in atherosclerosis and cardiovascular disease.13–17 sPLA2-IIA and the more recently cloned sPLA2-V are members of a family of enzymes that hydrolyze the fatty acids at the sn-2 position of glycerophospholipids. Both enzymes have low molecular weight (14 kDa), are histidine and calcium dependent, rich in disulfide bonds, are basic, and share structure similarities.18 Several of these properties stabilize and enhance their activity in the extracellular milieu. The genes of sPLA2-IIA and sPLA2-V enzymes are located at close positions in homologous regions in mouse chromosome 4 and human chromosome 1 and share the same promoter.19 This region was identified as an atherosclerosis susceptibility locus in the LDL receptor–deficient mouse and is considered a human candidate locus.20 The C57BL/6 mouse strain is a natural knockout of sPLA2-II because a frame shift mutation in exon 3 blocks gene translation.21 Therefore, either sPLA2-IIA does not contribute to atherogenesis in this mouse strain, or other(s) sPLA2 compensates its absence. On the other hand, the human sPLA2-IIA transgenic mouse is more susceptible to atherosclerosis than its littermates that only express the group V.13,16 This suggests that the expression of both enzymes may contribute to lesion formation. The group V sPLA2 is also present in human atherosclerotic lesions, but the cell source and regulation of sPLA2-V activity in lesions are unknown.22 Here, we report on the immunohistochemical localization and cell association of sPLA2-V in human and mouse lesions. We compared the mRNA expression in human lesions and vascular cells, the activities on lipoproteins, and modulation by extracellular arterial proteoglycans of sPLA2-V and sPLA2-IIA. In addition, we investigated in mouse models the effect of a Western diet and acute inflammation on the aortic expression of the enzymes.
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Materials and Methods |
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The Materials and Methods section is available online at http://atvb.ahajournals.org.
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Results |
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Immunohistochemical Staining of sPLA2-V in Human Lesions
The specificity of all used antibodies was evaluated by Western blotting, and no cross-reactivity of the antibodies against the 2 enzymes was detected (supplemental Figure I, available online at http://atvb.ahajournals.org). The antibodies against sPLA2-IIA that we used in our previous studies5,23 were also specific and did not cross-react with sPLA2-V. Figure 1 shows serial sections of 3 human atherosclerotic lesions. Figure 1A, 1D, 1G, 1J, 1N, and 1O are from an advanced lesion characterized by a thick intima and a well-formed necrotic lipid core. The second column (Figure 1B, 1E, 1H, 1K, 1L, 1P, and 1Q) shows sections from an intermediate type of aortic lesion characterized by a thick neointima with foam cells and a defined media, still with no tissue damage. The third column (Figure 1C, 1F, 1I, 1M, and 1R) shows sections from an advanced type of lesion in coronary artery characterized by a confluent mass of extracellular lipids (lipid core) and a structural altered intima. Actin-positive smooth muscle cells (SMCs) were present in the media and intima in all 3 lesion types (Figure 1A through 1C, arrows). CD68-positive macrophages were present only in the intima and lipid core of the lesions (Figure 1D through 1F, arrows). Immunostained sPLA2-V (Figure 1G through 1I, double arrows; 1N and 1O) was associated with SMCs colocalizing with actin in the media in intermediate lesions and the neointima of more advanced lesions. sPLA2-V was detected only extracellularly surrounding macrophages (M
) foam cell–rich areas and cholesterol crystals (Figure 1G through 1J and 1L and 1M, arrows). sPLA2-V was also detected in the endothelium of advanced lesions (Figure 1S and 1T, arrow) colocalizing with the marker for endothelial cells, von Willebrand factor (vWF), in serial consecutive sections (Figure 1U, arrow). vWF-positive endothelial cells in the vasa vasorum also showed positive immunostaining with sPLA2-V (Figure 1V and 1Z, respectively, arrows). sPLA2-V was not present in the adventitia, where we have previously shown sPLA2-IIA to be prominent4 (Figure 1B and 1H; supplemental Figure II). All the respective negative controls were devoid of staining (Figure 1P through 1R and 1W and 1Y).
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Immunohistochemical Staining of sPLA2-V in Mouse Lesions
Figure 2 shows serial sections from lesions of 2 individual apolipoprotein E and low-density lipoprotein receptor (apoExLDLr) double deficient mice (Figure 2A through 2E and 2H). There were similarities in the immunohistochemical distribution of sPLA2-V and that described above for human lesions, with the exception that the enzyme was not detected in mice endothelium (supplemental Figure III). This could have been caused by endothelium disruption during perfusion. Immunostaining showed shared areas positive for sPLA2-V (Figure 2A and 2E, arrows) and apoB (Figure 2B and 2F, arrows) using serial consecutive sections. More extensive colocalization was observed between macrophage-rich areas (Figure 2D and 2H) and sPLA2-V (Figure 2A and 2E) indicated with stars. Colocalization of sPLA2-V (Figure 2E) with actin-positive cells was also observed (Figure 2G, arrowheads).
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mRNA Expression of sPLA2-V and sPLA2-IIA in Human Vascular Cells, Human Lesions, and CD14-Positive Macrophages From Carotid Artery Lesions
The levels of sPLA2-IIA mRNA were 1000-fold higher than those of sPLA2-V in all 3 different sources of SMCs in culture, but the relative order of expression for different cells was similar (Figure 3). However, no expression of sPLA2-IIA was detected in M, M-loaded with lipids by incubation with acetylated LDL, or in arterial endothelial cells, whereas low levels of sPLA2-V mRNA were consistently present in these cells. The expression levels for both enzymes in human fibrotic lesion samples and CD14-positive lesion macrophages were different between samples (donors) but always 
2-fold higher for sPLA2-IIA than sPLA2-V (supplemental Figure IV). Expression levels of the housekeeping gene, 36B4, were similar between the different tissue samples and cultured cells (data not shown).
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Activity of Recombinant sPLA2-IIA and sPLA2-V on Human Serum and Lipoproteins
Both enzymes were equally active hydrolyzing phosphoethanolamine micelles and showed substrate specificity (supplemental Figure V). At equal enzyme molar concentrations (14 nmol/L or 200 ng/mL), sPLA2-V but not sPLA2-IIA hydrolyzed lipoprotein phospholipids in human sera and phospholipids of isolated very low-density lipoprotein (VLDL), LDL, and high-density lipoprotein (HDL; supplemental Figures VI and VII). Kinetic analysis showed that the VLDL surface phospholipids was the preferential substrate for sPLA2-V with a Km=546 µmol/L (substrate concentration that gives one-half the maximum velocity), followed by HDL and LDL with a Km of 1320 µmol/L and 3000 µmol/L, respectively (Figure 4). High-performance liquid chromatography analysis of all lipid classes in VLDL, LDL, and HDL incubated 24 hours with recombinant sPLA2-V showed a decrease in PC content of all lipoproteins. The phosphatidylethanolamine content was also decreased significantly in VLDL and LDL but not in HDL. This was accompanied by a significant increase in the corresponding lyso-phospholipids (Table). No changes were observed in other lipid classes (data not shown), thus indicating that sPLA2-V is specific for lipoprotein phospholipids. Complex formation of LDL with proteoglycans can contribute to retention of the LDL in the intima.24 We found that treatment with sPLA2-V increased the LDL–proteoglycans complex formation 20- to 25-fold. Using similar conditions, treatment of LDL with sPLA2-II resulted in no increase of the LDL–proteoglycans complex (supplemental Figure VIII).
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) and -free (
); sPLA2-V proteoglycans-bound (•) and -free (
). Values are means of duplicate values and are representative of 3 separate experiments.
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Interaction of sPLA2 With SMC Proteoglycans
sPLA2-IIA resides in the extracellular intima associated to proteoglycans, a situation that facilitates its action on lipoproteins also bound to the sulfated polysaccharides. The immunohistochemical results discussed above suggest that this could also occur with the group V enzyme (Figure 1). Gel mobility shift assay with metabolically labeled chondroitin-6-sulfate proteoglycans synthesized by human aortic SMCs showed that SPLA2-IIA was bound to proteoglycans with an apparent affinity constant (kd) of 19 nmol/L, whereas sPLA2-V bound with a lower-affinity kd of 951 nmol/L (Figure 5A). To study the effect of binding to proteoglycans on the enzymatic activity, LDL was incubated with increasing concentrations of free or proteoglycans-bound sPLA2-IIA and sPLA2-V. These experiments indicated that LDL is a better substrate for sPLA2-V than for sPLA2-IIA, corroborating results shown in supplemental Figure VI. More important, the data in printed Figure 5B demonstrate that when sPLA2-V was bound to proteoglycans, the hydrolysis of LDL phospholipids increased significantly. This upregulation of enzymatic activity on LDL phospholipids by binding to proteoglycans was not observed for sPLA2-IIA under similar conditions (Figure 4B).
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Induction of sPLA2-V and sPLA2-IIA Expression in Mouse Aorta
After 4 weeks on a Western diet (0.15% cholesterol, 21% cacao fat), sPLA2-V mRNA and protein were induced significantly in the aortas of C57BL/6 mice compared with animals on chow diet (Figure 5A). Furthermore, the apoExLDL receptor double-deficient mice, which develop hyperlipidemia and spontaneous atherosclerosis without a Western diet, showed elevated sPLA2-V protein expression in aorta similar to that of C57BL/6 on the Western diet (Figure 5B). There was no effect of the Western diet treatment on the spontaneous high levels of enzyme expression in the double knockout mice. On the other hand, acute inflammation triggered by an intraperitoneal injection with lipopolysaccharide (5 mg/kg) lipopolysaccharide did not change sPLA2-V expression in C57BL/6 mice but induced significantly the expression of sPLA2-IIA in the aorta of the mice transgenic for this human enzyme. Treatment with the Western diet did not affect the aortic expression of sPLA2-IIA in the transgenic mice, but similar to the C57BL/6 mice, it increased the expression of sPLA2-V (data not shown).
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Discussion |
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Expression of different phospholipase A2 enzymes in arteries may represent redundant activities because of similar properties. However, our results indicate that group IIA and V sPLA2 have dissimilar characteristics that could differentially modulate their postulated contribution to atherosclerosis. We found strong immunostaining of sPLA2-V extracellularly surrounding macrophage-like foam cells and in lipid-rich core areas. SPLA2-V was also present in SMCs in the media and neointima of intermediate and advanced lesions. However, only endothelial cells of advanced lesions showed positive immunostaining for sPLA2-V colocalizing with vWF. SPLA2-V was not detected in adventitia (Figure 1; supplemental Figure II). This tissue distribution of sPLA2-V in atherosclerotic lesions differs in some aspects from that described previously for group IIA sPLA2 by our laboratory and other laboratories.4,23,25–28 These apparent differences should be confirmed using common serial sections of the same tissue samples immunostained with antibodies specific against each enzyme. Levels of sPLA2-IIA and sPLA2-V mRNA in human lesions and in vitro human cell cultures indicate that cells present in lesions can produce the enzymes (supplemental Figure IV; Figure 3). We have previously shown that SMCs are the main source of sPLA2-IIA in vivo in arteries and in cell cultures.4,29 The present data indicate that nonproliferating human coronary SMCs and aortic SMCs have a higher mRNA expression for sPLA2-IIA and sPLA2-V than those of uterine SMCs, aortic endothelial cells, M
, and lipid-loaded M (Figure 3). There are large differences in expression levels of the 2 enzymes in vascular cells and human lesions (Figure 3; supplemental Figure IV) that could be caused by dissimilar transcription levels or differences in mRNA stability. Interestingly and in accord with the immunohistochemistry data, sPLA2-V mRNA but not sPLA2-IIA mRNA was detected in human endothelial cells and M and lipid-loaded M (Figure 3). sPLA2-IIA mRNA was detected in CD14-positive M from human lesions; however, no mRNA could be detected in THP-1–derived M in vitro, even when loaded with lipids. This discrepancy between ex vivo and in vitro RT-PCR results suggests that sPLA2-IIA gene transcription may require both differentiation and local exposure of macrophages to specific stimuli.30 In the C57BL/6 mouse, no group IIA enzyme is expressed.21 However, we found sPLA2-V expression in the plaques of apoExLDL receptor double knockout of the same strain (Figure 2; supplemental Figure III). The distribution pattern of sPLA2-V in mouse lesions was similar to that observed in human lesions. In addition, mouse showed shared areas positive for sPLA2-V and apoB. This could be caused by sPLA2-V entering the subendothelial space associated with apoB lipoproteins. However, we could not detect any association of the enzyme with lipoproteins after fractionation of serum in deuterium oxide gradients at physiological salt concentrations31 (supplemental Figure IX).
How sPLA2-IIA and sPLA2-V could modify circulating lipoproteins is not clear. We found that sPLA2-V but not sPLA2-IIA hydrolyzed lipoprotein phospholipids in the presence of complete serum. When purified plasma lipoproteins were used as substrates, the sPLA2-V preferentially hydrolyzed the phospholipidsin VLDL (Km=546 µmol/L), followed by those of HDL (Km=1.3 mmol/L) and LDL (Km=3 mmol/L; supplemental Figures VI and VII). Differences in sphingomyelin content on the lipoproteins surface monolayer may be responsible in part for the dissimilar activities observed.32 The group IIA sPLA2 did not hydrolyze phospholipids of any of the native lipoproteins (supplemental Figure VI). SPLA2-V has tryptophan residues in the interfacial binding region, which are absent in sPLA2-IIA.33 This probably enables sPLA2-V but not type IIA to penetrate and hydrolyze phospholipid monolayers from and lipoproteins in extracellular fluid.
Treatment with sPLA2-V increased the association of LDL with arterial proteoglycans (supplemental Figure VIII), thus suggesting that it is better suited than group II sPLA2 for acting on lipoproteins in the extracellular arterial intima. We speculate that modification of apoB-containing lipoproteins by extracellular sPLA2-V may contribute to 2 atherogenic mechanisms: the increased entrapment of partially modified LDL and the generation of proinflammatory lipid products.7,34 This hypothesis is supported by recent data showing that sPLA2-V–modified LDL induces foam cell formation by a process that involves proteoglycans.35 However, in spite of VLDL being a better substrate for the type V enzyme, we found no consistent increase of its binding to proteoglycans, probably because of the much lower affinity of proteoglycans for triglyceride-rich particles.36 The consequences of HDL hydrolysis by sPLA2-V are unknown and deserve further investigation because a PC-deficient lipoprotein in the intima could be a poor acceptor of excess cell cholesterol.37
Proteoglycans in the intima may not only contribute to the extracellular accumulation of the 2 enzymes but also to enhancing its activity. sPLA2-IIA associated to proteoglycans with higher affinity than sPLA2-V (Figure 5A). These differences are probably caused by the higher content of basic amino acids in sPLA2-IIA. However, the binding of sPLA2-V to proteoglycans resulted in a more significant increase in its capacity to hydrolyze LDL phospholipids than for sPLA2-IIA (Figure 5B). Mutational studies indicate that in human sPLA2-V, the interfacial-binding surface is separated from its glycosaminoglycan-binding surface, but in sPLA2-IIA, these areas partially overlap, and the glycosaminoglycan-binding surface is more diffuse.33 Such differences suggest that in sPLA2-V, binding to proteoglycans may increase the exposure of the interfacial catalytic domain, thus facilitating the interaction with the substrate. In contrast, the binding of sPLA2-IIA to proteoglycans may block the interfacial domain and, as a consequence, impair association with the substrate.
Despite group IIA and V sPLA2 enzymes being structurally similar, we found that a hyperlipidemic high-fat diet upregulates the expression in aorta of group V but not that of the group IIA. On the other hand, an acute inflammatory stimulus increased group IIA but not group V aortic expression (Figure 5). The response of sPLA2-IIA to inflammatory stimuli is well known.38,39 However, we believe that our finding of the effect of dyslipidemia on the type V enzyme is novel. We speculate that this phenomenon may be related to the described low-level inflammation associated with hyperlipidemia.40
In conclusion, our results showed clear differences between the 2 enzymes in the expression levels in vascular cells and in their ability to use human lipoproteins in serum as substrates. They also differ in the functional response to associations with arterial proteoglycans. Interestingly, in the mice models used, the enzymes differ in their response to high-fat diet and inflammatory challenge. The described properties profiles of these enzymes suggest that they can affect atherosclerosis by different pathways.
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Acknowledgments |
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This research was conducted with the financial support of the Swedish Heart-Lung Foundation and AstraZeneca, R&D, Mölndal, Sweden. The authors thank Germán Camejo for critical review of this manuscript.
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Footnotes |
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Original received November 10, 2005; final version accepted March 28, 2006.
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References |
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1. Small DM. Progression and regression of atherosclerotic lesions. Insights from lipid physical biochemistry. Arteriosclerosis. 1988; 8: 103–129.
2. Camejo G, Hurt E, Romano M. Properties of lipoprotein complexes isolated by affinity chromatography from human aorta. Biomed Biochim Acta. 1985; 44: 389–401.
3. Daugherty A, Zweifel BS, Sobel BE, Schonfeld G. Isolation of low density lipoprotein from atherosclerotic vascular tissue of Watanabe heritable hyperlipidemic rabbits. Arteriosclerosis. 1988; 8: 768–777.
4. Hurt-Camejo E, Anderssen S, Standal R, Rosengren B, Sartipy P, Stadberg E, Johansen B. Localization of non pancreatic secretory phospholipase A2 in normal and atherosclerotic arteries: activity of the isolated enzyme on low density lipoprotein. Arterioscler Thromb Vasc Biol. 1997; 17: 300–309.
5. Sartipy P, Johansen B, Camejo G, Rosengren B, Bondjers G, Hurt-Camejo E. Binding of human phospholipase A2 type II to proteoglycans: differential effect of glycosaminoglycans on enzyme activity. J Biol Chem. 1996; 271: 26307–26314.
6. Schissel SL, Jiang X-C, Tweedie-Hardman J, Jeong T-S, Hurt-Camejo E, Najib J, Rapp JH, Williams KJ, Tabas I. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. J Biol Chem. 1998; 273: 2738–2746.
7. Camejo G, Hurt-Camejo E, Wiklund O, Bondjers G. Association of apoB lipoproteins with arterial proteoglycans: pathological significance and molecular basis. Atherosclerosis. 1998; 139: 205–222.
8. Hakala JK, Öörni K, Pentikäinen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb Vasc Biol. 2001; 21: 1053–1058.
9. Hurt-Camejo E, Camejo G, Peilot H, Öörni K, Kovanen P. Phospholipase A2 in vascular disease. Circ Res. 2001; 89: 298–304.
10. Chang MY, Tsoi C, Wight Tn, Chait A. Lysophophatidylcholine regulates synthesis of biglycan and the proteoglycan form of macrophage colony stimulating factor. Arterioscler Thromb Vasc Biol. 2003; 23: 809–815.
11. Rinker KD, Kirkpatrick AP, Ting-Beall HP, Shephered RD, Levin JD, Irick J, Thomas JL, Truskey GA. Linoleic acid increases monocyte deformation and adhesion to endothelium. Atherosclerosis. 2004; 177: 275–285.
12. Benitez S, Camacho M, Arcelus R, Vila L, Bancells C, Ordonez-Llanos J, Sanchez-Quesada JL. Increased lysophosphaidylcholine and non-esterified fatty acid content in LDL induces chemokine release in endothelial cells. Relationship with electronegative LDL. Atherosclerosis. 2004; 177: 299–305.
13. Ivandic B, Castellini LW, Wang X-P, Qiao J-H, Mehrabian M, Navab M, Fogelman AM, Grass DS, Swanson ME, Beer MCD, Beer FD, Lusis AJ. Role of group II secretory phospholipase A2 in atherosclerosis. 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2. Arterioscler Thromb Vasc Biol. 1999; 19: 1284–1290.
14. Hurt-Camejo E, Paredes S, Masana L, Camejo G, Sartipy P, Rosengren B, Pedreno J, Vallve JC, Benito P, Wiklund O. Rheumatoid arthritis patients have elevated levels of small low density lipoprotein with high affinity for arterial matrix components: possible contribution of phoshoplipase A2 to this atherogenic profile. Arthritis Rheum. 2001; 44: 2761–2767.
15. Leinonen E, Hurt-Camejo E, Wiklund O, Mattson-Hultén L, Hiukka A, Taskinen M-R. Insulin resistance and adipocity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis. 2003; 166: 387–394.
16. Tietge UJF, Pratico D, Ding T, Funk C, Hildebrand R, Berkel TV, Eck MV. Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress. J Lipid Res. 2005; 46: 1604–1614.
17. Boekholdt SM, Keller TT, Wareham NJ, Luben R, Bingham SA, Day NE, Sandhu MS, Jukema JW, Kastelein JJP, Hack CE, Khaw K-T. Serum levels of type II secretory phospholipase A2 and the risk of future coronary artery disease in apparently healthy men and women. The EPIC-Norfolk prospective population study. Arterioscler Thromb Vasc Biol. 2005; 25: 839–846.
18. Six DA, Dennis EA. The expanding superfamily of phospholipase A2 enzymes: classification and characterization. Biochim Biophys Acta. 2000; 1488: 1–19.
19. Tischfield J, Xia Y, Shih D, Klisak I, Chen J, Engle S, Siakotos A, Winstead M, Seilhamer J, Allamand V, Gyapay G, Lusis A. Low-molecular-weight, calcium-dependent phospholipase A2 genes are linked and map to homologous chromosome regions in mouse and human. Genetics. 1996; 32: 328–333.
20. Welch CL, Bretschger S, Latib N, Bezouevski M, Guo Y, Pleskac N, Liang C-P, Barlow C, Dansky H, Breslow JL, Tall AR. Localization of atherosclerosis susceptibility loci to chromosome 4 and 6 using the LDLr knockout mouse model. Proc Natl Acad Sci U S A. 2001; 98: 7946–7951.
21. Kennedy BP, Payette P, Mudgett J, Vadas P, Pruzanski W, Kwan M, Tang C, Rancourt DE, Cromlish WAA. Natural disruption of the secretory group II phospholipase A2 gene in inbred mouse strains. J Biol Chem. 1995; 270: 22378–22385.
22. Wooton-Kee CR, Boyanovsky BB, Nasser MS, Villiers WJd, Webb NR. Group V sPLA2 hydrolysis of low-density lipoprotein results in spontaneous particle aggregation and promotes macrophages foam cell formation. Arterioscler Thromb Vasc Biol. 2004; 24: 762–767.
23. Romano M, Romano E, Björkerud S, Hurt-Camejo E. Ultrastructural localization of secretory type II phospholipase A2 in atherosclerotic and nonatherosclerotic regions of human arteries. Arterioscler Thromb Vasc Biol. 1998; 18: 519–525.
24. Camejo G. The interaction of lipids and lipoproteins with the intercellular matrix of arterial tissue: its possible role in atherogenesis. Adv Lipid Res. 1982; 19: 1–53.
25. Menschikowski M, Kasper M, Lattke P, Schiering A, Schiefer S, Stockinger H, Jaross W. Secretory group II phospholipase A2 in human atherosclerotic plaques. Atherosclerosis. 1995; 118: 173–181.
26. Elinder LS, Dumitrescu A, Larsson P, Hedin U, Fostergård J, Claesson H-E. Expression of phospholipase A2 isoforms in human normal and atherosclerotic arterial wall. Arterioscler Thromb Vasc Biol. 1997; 17: 2257–2263.
27. Sartipy P, Johansen B, Gåsnik K, Hurt-Camejo E. Molecular basis for the association of group IIA phospholipase A2 and decorin in human atherosclerotic lesions. Circ Res. 2000; 86: 707–714.
28. Menschikowski M, Eckey R, Pietsch J, Auffenanger J, Kumpf R, Nelz P, Jaross W. Expression of human secretory group IIA phospholipase A2 is associated with reduced concentrations of plasma cholesterol in transgenic mice. Inflammation. 2000; 24: 227–237.
29. Peilot H, Rosengren B, Bondjers G, Hurt-Camejo E. IFN-gamma induces secretory group IIA phospholipase A2 in human arterial smooth muscle cells. Involvement of cell differentiation, STAT-3 activation and modulation byother cytokines. J Biol Chem. 2000; 275: 22895–22904.
30. Anthonsen M, Stengel D, Hourton D, Ninio E, Johansen B. Mildly oxidized LDL induces expression of group IIa secretory phospholipase A2 in human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol. 2000; 20: 1276–1282.
31. Davidsson P, Hulthe J, Fagerberg B, Olsson B-M, Hallberg C, Dahllöf B, Camejo G. A proteomic study of the apolipoproteins in LDL aubclasses in patients with the metabolic syndrome and type 2 diabetes. J Lipid Res. 2005; 46: 1999–2006.
32. Gesquiere L, Cho W, Subbaiah P. Role of group IIa and group V secretory phospholipase A2 in the metabolism of lipoproteins. Substrate specificities of the enzymes and the regulation of their activities by sphingomyelin. Biochemistry. 2002; 41: 4911–4920.
33. Cho W. Structure, function, and regulation of group V phospholipase A2. Biochim Biophys Acta. 2000; 1488: 48–58.
34. Williams KJ, Tabas I. Lipoprotein retention and clues for atheroma regression. Arterioscler Thromb Vasc Biol. 2005; 25: 1536–1540.
35. Boyanovsky BB, Westhuyzen DRVD, Webb NR. Group V secretory phsopholipase A2-modified low density lipoprotein promotes foam cell formation by a SR-A- and CD36-independnet process that involves cellular proteoglycans. J Biol Chem. 2005; 280: 32746–32752.
36. Olsson U, Camejo G, Bondjers G. Binding of a synthetic apolipoprotein B-100 peptide and peptide analogues to chondroitin-6-sulfate: effect of the lipid environment. Biochemistry. 1993; 32: 1858–1865.
37. Chung B-H, Franklin F, Liang P, Doran S, Cho BHS, Curcio CA. Phosphatidylcholine-rich acceptors, but not native HDL or its apolipoproteins, mobilize cholesterol from cholesterol-rich insoluble components of human atherosclerotic plaques. Biochim Biophys Acta. 2005; 1733: 76–89.
38. Laine VJO, Grass DS, Nevalainen TJ. Protection by group II phospholipase A2 against Staphylococcus aureus. J Immunol. 1999; 162: 7402–7408.
39. Tietge UJ, Maugeais C, Cain W, Rader DJ. Acute inflammation increases selective uptake of HDL cholesteryl esters into adrenals of mice overexpressing human sPLA2. Acta Physiol Scand. 2003; 285: E403–E411.
40. Lewis KE, Kirk EA, McDonald TO, Wang S, Wight TN, Wallick S, Andersson M, Aikawa K, Kahn SE. Increased in serum amyloid A evoked by dietary cholesterol is associated with increased atherosclerosis in mice. Circulation. 2004; 110: 540–545.
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B. B. Boyanovsky, P. Shridas, M. Simons, D. R. van der Westhuyzen, and N. R. Webb Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified LDL J. Lipid Res., April 1, 2009; 50(4): 641 - 650. [Abstract] [Full Text] [PDF]
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 N. Nijstad, H. Wiersma, T. Gautier, M. van der Giet, C. Maugeais, and U. J. F. Tietge Scavenger Receptor BI-mediated Selective Uptake Is Required for the Remodeling of High Density Lipoprotein by Endothelial Lipase J. Biol. Chem., March 6, 2009; 284(10): 6093 - 6100. [Abstract] [Full Text] [PDF]
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H. Sato, R. Kato, Y. Isogai, G.-i. Saka, M. Ohtsuki, Y. Taketomi, K. Yamamoto, K. Tsutsumi, J. Yamada, S. Masuda, et al. Analyses of Group III Secreted Phospholipase A2 Transgenic Mice Reveal Potential Participation of This Enzyme in Plasma Lipoprotein Modification, Macrophage Foam Cell Formation, and Atherosclerosis J. Biol. Chem., November 28, 2008; 283(48): 33483 - 33497. [Abstract] [Full Text] [PDF]
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 M. Pan, V. Maitin, S. Parathath, U. Andreo, S. X. Lin, C. St. Germain, Z. Yao, F. R. Maxfield, K. J. Williams, and E. A. Fisher Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control PNAS, April 15, 2008; 105(15): 5862 - 5867. [Abstract] [Full Text] [PDF]
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 P. T.E. Wootton, N. L. Arora, F. Drenos, S. R. Thompson, J. A. Cooper, J. W. Stephens, S. J. Hurel, E. Hurt-Camejo, O. Wiklund, S. E. Humphries, et al. Tagging SNP haplotype analysis of the secretory PLA2-V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study Hum. Mol. Genet., June 15, 2007; 16(12): 1437 - 1444. [Abstract] [Full Text] [PDF]
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 Z. Mallat, J. Benessiano, T. Simon, S. Ederhy, C. Sebella-Arguelles, A. Cohen, V. Huart, N. J. Wareham, R. Luben, K.-T. Khaw, et al. Circulating Secretory Phospholipase A2 Activity and Risk of Incident Coronary Events in Healthy Men and Women: The EPIC-NORFOLK Study Arterioscler Thromb Vasc Biol, May 1, 2007; 27(5): 1177 - 1183. [Abstract] [Full Text] [PDF]
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K. Oorni and P. T. Kovanen PLA2-V: A Real Player in Atherogenesis Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 445 - 447. [Full Text] [PDF]
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M. A. Bostrom, B. B. Boyanovsky, C. T. Jordan, M. P. Wadsworth, D. J. Taatjes, F. C. de Beer, and N. R. Webb Group V Secretory Phospholipase A2 Promotes Atherosclerosis: Evidence From Genetically Altered Mice Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 600 - 606. [Abstract] [Full Text] [PDF]
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M. Ohtsuki, Y. Taketomi, S. Arata, S. Masuda, Y. Ishikawa, T. Ishii, Y. Takanezawa, J. Aoki, H. Arai, K. Yamamoto, et al. Transgenic Expression of Group V, but Not Group X, Secreted Phospholipase A2 in Mice Leads to Neonatal Lethality because of Lung Dysfunction J. Biol. Chem., November 24, 2006; 281(47): 36420 - 36433. [Abstract] [Full Text] [PDF]
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F. C. de Beer and N. R. Webb Inflammation and Atherosclerosis: Group IIa and Group V sPLA2 Are Not Redundant Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1421 - 1422. [Full Text] [PDF]
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