© 2000 American Heart Association, Inc.
Clinical Research |
Molecular Basis for the Association of Group IIA Phospholipase A2 and Decorin in Human Atherosclerotic Lesions
From Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden (P.S., E.H.-C.), and the Department of Botany/UNIGEN Center for Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway (B.J., K.G.).
Correspondence to Peter Sartipy, Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg 413 45, Sweden. E-mail peter.sartipy{at}wlab.wall.gu.se
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Abstract |
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Abstract—Group IIA secretory nonpancreatic phospholipase A2 (snpPLA2) is associated with collagen fibers in the extracellular matrix of human atherosclerotic plaques. Decorin, a small proteoglycan (PG) carrying chondroitin/dermatan sulfate glycosaminoglycans (GAGs), forms part of the collagen network in human arteries. To explore whether snpPLA2 may be associated with collagen fibers via interaction with decorin, we performed (1) immunohistochemistry to compare the relative in vivo localization of snpPLA2 and decorin in human atherosclerotic tissue and (2) in vitro experiments to study the interaction between snpPLA2 and decorin. In atherosclerotic lesions, decorin was detected within the snpPLA2-positive part of the intima close to the media. Electrophoretic mobility shift assay showed that snpPLA2 binds to decorin synthesized by human fibroblasts. Native and GAG-depleted decorin enhanced the association of snpPLA2 to collagen types I and VI in a solid-phase binding assay. Furthermore, snpPLA2 bound efficiently to a recombinant decorin core protein fragment B/E (Asp45-Lys359). This binding was competed with soluble decorin and inhibited at NaCl concentrations >150 mmol/L. The decorin core protein fragment B/E competed better than dermatan sulfate for binding of snpPLA2 to decorin-coated microtiter wells. The enzymatic activity of snpPLA2 increased 2- to 3-fold in the presence of decorin or GAG-depleted decorin. The results show that snpPLA2 binds preferentially to the decorin protein core rather than to the GAG chain and that this interaction enhances snpPLA2 activity. As a consequence, this active extracellular enzyme may contribute to the pathogenesis of atherosclerosis by modifying lipoproteins and releasing inflammatory lipid mediators at places of lipoprotein retention in the arterial wall.
Key Words: atherosclerosis • decorin • group IIA phospholipase A2
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Group IIA secretory nonpancreatic phospholipase A2 (snpPLA2) is a 14-kDa calcium-dependent enzyme that hydrolyzes the sn-2 fatty acid acyl ester bond of phosphoglycerides to free fatty acids (FFAs) and lysophospholipids.1 These products can act as intracellular second messengers or be further metabolized into proinflammatory lipid mediators.2 Immunohistochemical studies demonstrated the presence of snpPLA2 in human arteries,3 and ultrastructural localization showed that some of the snpPLA2 was located along collagen fibers in the extracellular matrix of human atherosclerotic lesions.4 Most of the collagen in arterial intima is collagen types I and III. Interspersed between these is collagen type VI, which appears in all vascular layers.5 Several studies have shown that collagen interacts with decorin, a chondroitin/dermatan sulfate (CS/DS) proteoglycan (PG) of the SLRP family class I.6 7 Decorin is present in the arterial wall, and its distribution is different in healthy arteries from that of atherosclerotic plaques.8 When decorin is associated with collagen, both the core protein and the glycosaminoglycan (GAG) chain are still available for binding to other ligands, eg, transforming growth factor (TGF)-ß9 and LDL.10 These observations suggest that some of the extracellular snpPLA2 detected in the arterial intima of lesions may be associated with collagen fibers via its interaction with decorin.
The hypothesis of the potential involvement of snpPLA2 in the pathogenesis of atherosclerosis11 was recently reinforced with in vivo data.12 13 14 The proatherogenic mechanisms of snpPLA2 may be potentiated by the capacity of both snpPLA2 and apolipoprotein (apo) B lipoproteins to interact with sulfated PG/GAG.15 This may be a mechanism that contributes to colocalization of the enzyme and lipoproteins at cell membranes and extracellular space. However, the molecular basis for the interactions of snpPLA2 with extracellular matrix components and how this may locate and control enzyme activity at sites of lesion development needs to be clarified. In the present work, we performed immunohistochemistry to explore the relative distribution of decorin and snpPLA2 in human nonatherosclerotic and atherosclerotic tissue. We also studied, in vitro, the binding of snpPLA2 to decorin, the role of decorin in mediating the binding of snpPLA2 to collagen types I and VI, and how decorin modulates snpPLA2 activity.
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Materials and Methods |
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Immunohistochemistry
Human carotid artery segments were obtained from autopsy or surgery and quickly frozen and stored at -20°C until sectioning. Uterine arteries (used as nonatherosclerotic control tissue) were obtained from women undergoing hysterectomy. Atherosclerotic regions were defined by the presence of intima thickness accompanied by extracellular lipid accumulations, cholesterol crystals, and foam-cell and non–foam-cell macrophages.
Immunofluorescence staining was performed on atherosclerotic (n=9) and nonatherosclerotic (n=4) arteries.3 Mouse monoclonal antibody (mAb) BF1 was used to detect snpPLA2. An antibody generated against smooth muscle cell actin, HHF-35, recognized vascular smooth muscle cells. Decorin was detected by an mAb generated against the core protein moiety.16 In addition, some sections were incubated with or without chondroitinase ABC (ChABC). Standard hematoxylin/eosin staining for routine histological evaluation of the sections was also performed.
Isolation and Characterization of PG
Confluent human skin fibroblasts maintained in Eagle’s minimum
essential medium in bottles coated with collagen type I17
were incubated for 3 days with medium containing
L-[4,5-3H]leucine and
[35S]sulfur at final specific activities of 17
µCi/mL and 33 µCi/mL, respectively. Conditioned medium was
collected and supplemented with protease inhibitors.
PGs, isolated from conditioned medium,18 were digested with chondroitinase AC (ChAC), chondroitinase B (ChB), or heparitinase I (HS I) and analyzed by SDS-PAGE.19 PGs were also digested with ChABC, and Western blot was performed essentially as described.18
In Vitro Interactions of snpPLA2 With Decorin and
Collagen
snpPLA2 was purified from conditioned
medium from a transfected CHO cell line20 as
described.21 Binding of snpPLA2 to
fibroblast-derived PG was analyzed by electrophoretic mobility
shift assay (EMSA).22
Expression and purification of a recombinant decorin core protein fragment representing Asp45-Lys359 (B/E) was done essentially as described.23
Microtiter wells were coated with collagen type I or VI or FFA-free BSA.6 Native decorin (from bovine articular cartilage) or decorin digested with ChABC was added to some wells. Nonbound decorin was determined in the supernatants after incubation.24 snpPLA2 was diluted with D-PBS and added to the wells in increasing concentrations. After incubation, the activity of bound snpPLA2 was determined by measuring generation of FFA from PC mixed micelles (prepared as described below) with a commercial kit (NEFA-C).
Microtiter wells were coated with the B/E fragment. In some experiments, snpPLA2 was added directly to the B/E-coated wells. In a second set of experiments, a constant concentration of snpPLA2 (290 nmol/L) was mixed with increasing concentrations of decorin before it was added to the B/E-coated wells. In a third set of experiments, snpPLA2 (290 nmol/L) was added to B/E-coated wells in D-PBS supplemented with NaCl. In all experiments, the activity of snpPLA2 retained in the B/E-coated wells was determined as described above.
snpPLA2 Activity
PC mixed micelles were prepared as described.21
Human LDL was isolated from healthy fasted male
volunteers.25 snpPLA2 and decorin or
GAG-depleted decorin were preincubated (30 minutes, room temperature)
before substrate was added. snpPLA2 activity was
determined by measuring release of FFA during the incubations.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Immunohistochemistry
The selectivity of the mAb generated against decorin was initially tested and confirmed on sections of normal human skin segments (data not shown). In human nonatherosclerotic arteries (Figure 1
), prominent staining of decorin was
detected by immunofluorescence only in the
adventitia. In sections of atherosclerotic lesions (Figure 2) showing a thickened intima and part of
the media, decorin was detected mainly in the layer of intima close to
the media and less in the subendothelial part of the
intima, as shown in Figure 2A and 2B.
Immunostaining of neighboring sections with mAb HHF-35
(Figure 2C and 2D) shows 2 regions within atherosclerotic
lesions that are enriched in smooth muscle cells. One region is the
subendothelial intima, which contains a belt of mostly
spindle-shaped smooth muscle cells. The other region is the media and
the medial intima. Immunostaining with mAb BF1 (Figure 2E and 2F) shows that most
snpPLA2-positive cells have a distribution
similar to that of the actin HHF-35–positive cells. Other
snpPLA2-positive cells that are not smooth muscle
cells (HHF-35–negative) were also detected in the arterial
intima (Figure 2E and 2F). On the basis of their morphology and
findings from earlier studies, these additional cells may be
macrophages.3 In advanced atherosclerotic lesions
(Figure 3), decorin was detected in the
plaque core close to the media overlapping with
snpPLA2 staining. Some atherosclerotic sections
were also preincubated with ChABC before immunostaining
was performed (see online supplementary information;
http://www.circresaha.org). In brief, the
immunohistological detection of
snpPLA2 increased after ChABC treatment in
regions corresponding to areas that also stain positive for decorin.
This suggests that the removal of the GAG moiety unmasks but does not
remove snpPLA2-antigen associated with decorin. A
summary of the immunohistological detection of decorin
and snpPLA2 is presented in the
Table. The extent of decorin
distribution in intima corresponds with severity of the lesion and
coincides with snpPLA2 staining, except that more
areas are positive for snpPLA2 than decorin.
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Isolation and Characterization of PG
Decorin is a quiescence-inducible gene in
fibroblasts,26 and reverse transcription–polymerase chain
reaction evaluation of total RNA isolated from the cells indicated a
high expression of decorin 1 to 7 days postconfluence (data not shown).
The PG preparation obtained from conditioned medium contained mainly
decorin (Figure 4A and 4B). The band
migrating at 
100 kDa was totally degraded by ChB, indicating the
presence of DS. A protein band with a molecular weight of 45 to 50 kDa,
corresponding to the size of the core protein of decorin, was left
after digestion with ChB, and it was identified as the decorin core
protein by Western blot analysis. The PG preparation also
contained a small proportion of a material retained at the top of the
gel that was susceptible to HS I digestion (perlecan-like).
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In Vitro Interactions of snpPLA2 With Decorin and
Collagen
We studied the interaction of snpPLA2 with
decorin and with decorin bound to collagen type I or VI in 2 different
in vitro models: (1) EMSA with decorin isolated from human fibroblasts
and (2) a solid-phase binding assay using collagen and
collagen-decorin–coated microtiter wells.
In the EMSA assay (Figure 4C
), the intensity of the band
corresponding to free decorin decreases in the presence of 0.25
µmol/L of snpPLA2 and also with 0.5
µmol/L of snpPLA2. Furthermore, the band
corresponding to decorin migrates differently and becomes wider in the
presence of 0.5 µmol/L of snpPLA2 compared
with the control (without snpPLA2). At
concentrations >1 µmol/L of snpPLA2,
there is no free decorin, and all decorin molecules have formed
complexes with snpPLA2 and remain at the origin
of the gel. These results indicate that snpPLA2
binds to decorin in vitro at physiological ionic
conditions.
The possibility that decorin may serve as a link between collagen
fibers and snpPLA2 was investigated with a
microtiter-well binding assay. The wells were first coated with
collagen type I or VI, and then decorin was added. The wells coated
with collagen type VI bound more decorin (370±50 ng, n=9) than the
wells coated with collagen type I (160±60 ng, n=16). Control wells
contained either collagen type I or VI or BSA. Measuring
snpPLA2 activity monitored binding of
snpPLA2. snpPLA2 did not
bind to the wells coated only with collagen type I or with BSA (Figure 5A). However,
snpPLA2 was able to bind to collagen type VI
(Figure 5B). The binding to collagen type VI was higher than
that of control wells coated with BSA. This suggests that
snpPLA2 may associate with collagen type VI even
in the absence of decorin. Interestingly, the addition of decorin to
collagen-coated wells significantly enhanced the binding of active
snpPLA2 to both collagen types I and VI (Figure 5A and 5B), indicating that decorin may mediate binding of
snpPLA2 to collagen fibers.
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snpPLA2 may bind to decorin through the GAG
and/or the protein moiety of the PG. To discriminate between these
possibilities, we performed experiments with decorin and decorin
pretreated with ChABC. There was no difference in the amount of active
snpPLA2 binding to untreated decorin or
GAG-depleted decorin in plates coated with collagen type VI (Figure 5C). Importantly, the GAG moiety in decorin was totally
degraded, according to analysis of ChABC-treated decorin by
SDS-PAGE (data not shown). These results suggest that
snpPLA2 binds to GAG-depleted decorin, possibly
through a direct interaction with the core protein of decorin. Notably,
in similar experiments performed with versican-coated plates, the
retention of active snpPLA2 decreased
significantly after GAG digestion (see online supplementary
information; http://www.circresaha.org).
To further analyze the binding of snpPLA2
to the core protein of decorin, a recombinant core protein fragment of
human decorin, Asp45-Lys359 (fragment B/E), was expressed. Compared
with the complete processed and secreted decorin core protein, this
fragment lacks 14 amino acid residues at the N-terminal, it carries no
GAG chain, and it is not glycosylated. snpPLA2
was efficiently retained in B/E-coated wells (Figure 6A). The wells contained 910±430 ng
(n=9) of the B/E fragment. The binding to the BSA-coated wells was low.
It was possible to compete the binding of snpPLA2
to immobilized B/E by soluble decorin (Figure 6B).
At the highest concentration of competitor (0.2 µg/µL), only
20% of the snpPLA2 was bound, compared with
100% snpPLA2 bound in the absence of competitor.
The binding of snpPLA2 to B/E-coated wells
appears to be mediated mainly by electrostatic interactions, because
the binding was almost completely inhibited by increasing the NaCl
concentration up to 1 mol/L in the binding buffer (Figure 6C).
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Experiments were also performed with decorin-coated microtiter wells
using the B/E fragment or DS as competitors. The B/E fragment was more
efficient in competing for binding of snpPLA2 to
decorin-coated wells compared with DS. Preincubation of 290 nmol/L
snpPLA2 together with 0.12 µg/µL of B/E
(Mw 35 kDa) or DS
(Mw 11 to 25 kDa) reduced the binding of
snpPLA2 to the decorin-coated wells to 40% (B/E)
and 90% (DS), compared with 100% binding in the absence of
competitors. Ten times higher concentrations of the competitors further
reduced the binding of snpPLA2 to the
decorin-coated wells to 18% and 70%, respectively.
Effect of Decorin on the Activity of snpPLA2
To investigate whether the interaction with decorin could affect
the enzyme activity, increasing concentrations of decorin or
GAG-depleted decorin were incubated with snpPLA2.
snpPLA2 activity was increased in the presence of
decorin when PC micelles or LDL was used as substrate presenting
structures (Figure 7). Interestingly, a
similar enhancing effect on snpPLA2 activity was
observed with untreated decorin and with GAG-depleted decorin. These
results support the results from the microtiter binding assay
indicating that snpPLA2 binds to the core protein
of decorin and that this interaction enhances
snpPLA2 activity.
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Discussion |
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snpPLA2 displays 3 biochemical properties of a secretory enzyme. First, the cDNA encodes a 144-amino-acid protein including a 20-amino-acid signal peptide. Second, snpPLA2 has 7 disulfide bridges, which makes it a very stable protein against proteolysis and nonenzymatic hydrolysis. Third, it requires millimolar concentrations of calcium for its activity. The immunofluorescence results in the present study show that staining for snpPLA2 coincides with regions that stain positively for the extracellular matrix PG decorin in human atherosclerotic arteries. The distribution of decorin and snpPLA2 in nonatherosclerotic and atherosclerotic arteries was similar to what has been reported.3 8 27 The immunofluorescence results on arterial wall sections indicate colocalization of snpPLA2 and decorin. However, the relative differences of the signal intensities suggest that other matrix components besides collagen-associated decorin may also bind snpPLA2. Hence, the presence of extracellular snpPLA2 is not dependent on decorin, because snpPLA2 shows a wider distribution pattern than decorin.
Decorin is one of the several PGs known to accumulate in human atherosclerotic plaques, and it colocalizes with collagen.27 Its major functions appear to be assembly of collagen fibers, binding and regulation of growth factor activity, and control of cell growth.7 Decorin possesses 2 main collagen-binding sites23 that do not involve the CS/DS moiety. The single GAG chain located at Ser7 close to the N-terminal of the core protein protrudes away from decorin and is free to interact with other proteins. The results obtained in this work with 2 different in vitro binding assays show that snpPLA2 is able to interact with both the GAG moiety and the core protein of decorin at physiological salt and pH conditions. The mobility of decorin in the EMSA experiments, in which snpPLA2 was present in large excess, was inhibited, suggesting interaction with the GAG side chain. The mobility of the PG in the gel electrophoresis is dependent on its negatively charged GAG. Association of the snpPLA2 with the GAG appeared to be responsible for the inhibited mobility. However, the solid-phase binding assay, in which decorin and snpPLA2 were present in similar amounts, showed that snpPLA2 also binds to GAG-depleted decorin. These results were confirmed with experiments performed with a human recombinant decorin core protein fragment (Asp45-Lys359). Furthermore, this fragment competed more efficiently than DS for snpPLA2 binding to immobilized decorin, indicating a higher affinity of snpPLA2 for the decorin core protein fragment compared with the DS side chain. Taken together, these results indicate that snpPLA2 preferentially binds to the core protein of decorin. Other proteins, such as TGF-ß and apoB,9 10 have also been shown to interact with collagen-bound decorin.
Versican, a high-molecular-weight interstitial CS-rich PG, is abundant in the arterial intima and accumulates especially in the early phase of lesion development.5 Previous studies have shown that versican isolated from human arterial smooth muscle cell binds to snpPLA2 in vitro mainly via the GAG moiety.21 The results presented in this study support this observation, and degradation of the GAG reduced the capacity of immobilized versican to bind exogenous snpPLA2. There are regional differences in the distribution of decorin and versican in the normal and atherosclerotic arterial wall, suggesting that these PGs may have different functional roles during lesion progression.8
Decorin increased the enzymatic activity of snpPLA2 independently if the substrate presenting structure was LDL or PC micelles. LDL is known to bind to GAG of arterial PG, a process considered to be a key event in atherogenesis.28 29 Interestingly, decorin was reported to link LDL and collagen fibers in vitro through its CS/DS chain.10 In addition, apo(a) from Lp(a) binds to the core protein of decorin.30 These findings suggest that binding of snpPLA2 and apoB-containing lipoproteins to CS/DS PGs may facilitate their colocalization in the arterial intima. This may enhance the hydrolysis of phospholipids at places of apoB lipoprotein deposition in the arterial wall.
The levels of extracellular snpPLA2 appear to be
regulated through both secretion of already synthesized enzyme and
modulation of its gene expression. Inflammatory cytokines,
including interleukin (IL)-1ß and tumor necrosis factor-
, are
reported to stimulate the secretion of
snpPLA2.31 32 In contrast, TGF-ß
and platelet-derived growth factor are reported to inhibit
snpPLA2 expression.33 Furthermore,
these cytokines and growth factors are reported to modulate the
expression of different PGs by arterial smooth muscle
cells.34 Interestingly, the expression of
snpPLA2 and decorin is regulated similarly by
IL-1ß and TGF-ß. These findings suggest that the distribution of
snpPLA2 and decorin in the arterial
wall may be modulated by local inflammatory conditions characteristic
for atherogenesis.35 As a consequence, one may also
expect modulation of the local activity of extracellular
snpPLA2 in the arterial wall by the
cytokines.
Taken together, these data suggest that PGs known to accumulate in atherosclerosis8 might bind snpPLA2 secreted by smooth muscle cells and thereby be partially responsible for the abundant extracellular snpPLA2 detected in arterial plaques,3 4 thus reinforcing the hypothesis that the presence of active extracellular snpPLA2 in the arterial wall may contribute to lipoprotein modification and generation of lipid mediators at places of atherosclerotic plaque formation and progression.
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Acknowledgments |
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This work was supported by grants from the Medical Research Council (project No. 12129 to E.H.-C.), the Swedish Heart and Lung Foundation (project No. 61538 to E.H.-C.), and AstraZeneca R&D, Mölndal, Sweden. The authors are grateful to Prof Germán Camejo for valuable discussions during the course of this work and also for critically reading the manuscript.
Received December 22, 1999; accepted February 3, 2000.
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