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Originally published In Press as doi:10.1194/jlr.M400019-JLR200 on July 16, 2004

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Journal of Lipid Research, Vol. 45, 1806-1812, October 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Atherosclerosis in perlecan heterozygous mice

Reeba K. Vikramadithyan*, Yuko Kako*, Guangping Chen*, Yunying Hu*, Eri Arikawa-Hirasawa{dagger}, Yoshihiko Yamada{dagger} and Ira J. Goldberg1,*

* Department of Medicine, Columbia University, New York, NY 10032
{dagger} National Institute of Dental and Craniofacial Research, Bethesda, MD 20892-4370

Published, JLR Papers in Press, July 16, 2004. DOI 10.1194/jlr.M400019-JLR200

1 To whom correspondence should be addressed. e-mail: ijg3{at}columbia.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The hypothesis that lipoprotein association with perlecan is atherogenic was tested by studying atherosclerosis in mice that had a heterozygous deletion of perlecan, the primary extracellular heparan sulfate proteoglycan in arteries. We first studied the expression of perlecan in mouse lesions and noted that this proteoglycan in aorta was found in the subendothelial matrix. Perlecan was also a major component of the lesional extracellular matrix. Mice with a heterozygous deletion had a reduction in arterial wall perlecan expression. Atherosclerosis in these mice was studied after crossing the defect into the apolipoprotein E (apoE) and LDL receptor knockout backgrounds. At 12 weeks, chow-fed apoE null mice with a heterozygous deletion had less atherosclerosis. However, at 24 weeks and in the LDL receptor heterozygous background, the presence of a perlecan knockout allele did not significantly alter lesion size.

Thus, it appears that loss of perlecan leads to less atherosclerosis in early lesions. Although this might be attributable to a decrease in lipoprotein retention, it should be noted that perlecan might mediate multiple other processes that could, in sum, accelerate atherosclerosis.

Supplementary key words heparan • low density lipoprotein receptor • apolipoprotein E • proteoglycans • lipoproteins


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Much of atherosclerosis research in the 20th century focused on the cholesterol hypothesis. The evidence that plasma cholesterol-containing lipoproteins cause atherosclerosis is indisputable. However, as was nicely summarized nearly 50 years ago (1), how these lipid-containing particles accumulate within the artery and then produce inflammatory reactions is still unclear. A refinement to the "infiltrative theory" has been an attempt to define the biochemical interactions that lead to this process. Because the lipoproteins are initially found in the extracellular space, they are thought to bind to protein or carbohydrate components of the extracellular matrix. Among the molecules that have been most studied in this respect are proteoglycans (2).

Within the artery are a number of classes of proteoglycans, complex proteins that contain highly negatively charged carbohydrates. There are several observations that support the proteoglycan-lipoprotein association hypothesis. 1) Dermatan/chondroitin sulfate proteoglycans are found in greater amounts in lesions (3, 4), and some classes of these proteins are found in regions that also contain apolipoprotein B (apoB) (5), the major protein component of LDL and remnant lipoproteins. 2) Complexes of proteoglycans and LDL have been isolated from arteries (6). 3) Prolonged incubations of proteoglycans and LDL will, in vitro, produce aggregates (7).

Of all the proteoglycans, the most heavily charged and most avid LDL binding are the heparan sulfate proteoglycans (8). Heparin, a highly charged carbohydrate of this class, has been studied because it interacts with apoB-containing lipoproteins (9, 10). This reaction, however, is most evident in low ionic strength solutions; in several reports, the proteoglycan-LDL complexes are dissociated by physiologic saline (9). Moreover, increasing LDL charge (e.g., via oxidation) decreases the proteoglycan-lipoprotein interaction (11).

One way to study the role of proteoglycans in atherosclerosis is to use genetically manipulated mice that have an alteration in proteoglycan production. Perlecan is a 450 kDa core protein containing three heparan sulfate chains of 70 kDa attached in domain I and an additional chain associated with domain V. Perlecan is the major heparan sulfate proteoglycan in the subendothelial matrix (12). This protein has a variety of actions and is essential for normal bone formation and neurological development; a homozygous deletion of perlecan in mice is lethal as a result of bone and neurological malformations (13). Within the vasculature, perlecan helps to stabilize the endothelial barrier and decrease the proliferation of smooth muscle cells (14); these are potentially antiatherogenic actions of perlecan. We first studied perlecan expression in normal and atherosclerotic mouse arteries and then tested whether a partial loss of perlecan alters atherosclerosis in the mouse.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Mouse housing and diets
Mice were maintained in a temperature-controlled (25°C) facility with a 12 h light/dark cycle and given free access to food and water, except when fasting blood specimens were obtained. Mice were fed either laboratory rodent chow (PMI Nutrition International, Inc.) or a Paigen diet (C13002; Research Diets, Inc.). Rodent chow contained 4.5% (w/w) fat; the Paigen diet contained 15% (w/w) fat, 1.25% (w/w) cholesterol, and 0.5% cholic acid.

Genetically altered mice
Heterozygous perlecan-deficient mice (13) were backcrossed to C57BL/6 mice for seven generations. These animals were crossed onto apolipoprotein E null (apoE0) mice or LDL receptor knockout mice in the same background that were purchased from Jackson Laboratory (Bar Harbor, ME).

Immunohistochemical staining for aortic perlecan
Aortas from male apoE0 mice fed a chow diet at different time points were embedded in OCT and snap frozen on dry ice. Ten micrometer frozen sections were fixed in cold acetone, and endogenous peroxidase was quenched with 3% H2O2/methanol. The sections were then stained with 1:100 rat monoclonal antibody against perlecan (Neo Marks, Inc.) at 37°C for 1 h, then at 4°C overnight. The antibody was detected with the standard Avidin Biotin Complex method (Vector Laboratories, Inc.) and 3-amino-9-ethyl carbazole (Zymed Laboratories) as the substrate. Positive staining is shown as red deposits. For a negative control, slides were incubated with nonimmune rat IgG (Sigma) in place of the first antibody.

Quantitative real-time PCR for the aortic perlecan gene
Total RNA was isolated from aortas of heterozygous LDL receptor-deficient mice and heterozygous perlecan mice in the heterozygous LDL receptor-deficient background using the RNeasy mini kit (Qiagen). The mRNA levels for perlecan were determined by SYBR green (Applied Biosystems) real-time PCR using 10–100 ng of total RNA. Primer sequences were selected from domain I, the potential heparan sulfate attachment domain (PubMed sequence NM008305; 201–408). The primer sequences are as follows: Prl-RT (forward), 5'-TACGCGGTCCATTGAG-3'; Prl-RT (reverse), 5'-AGATCCGTCCGCATTC-3'. The real-time PCR standard curve was constructed by using serial dilutions of mouse total RNA isolated from aortas. Data were normalized to mouse ß-actin.

Blood sampling
Fasting blood samples were obtained from mice after removal of food for 6 h in the morning. The animals were anesthetized with methoxyflurane and bled by retro-orbital phlebotomy into tubes containing anticoagulant (5 mM EDTA) using heparinized capillary tubes. Cholesterol and triglyceride were measured using kits from Sigma. Lipoproteins—VLDL (d < 1.006 g/ml), intermediate density lipoprotein/LDL (d = 1.006–1.063 g/ml), and HDL (d = 1.063–1.21 g/ml)—were separated by sequential density ultracentrifugation of plasma in a TLA 100 rotor (Beckman Instruments) (15).

Quantitative atherosclerosis analysis
Mice were killed and atherosclerosis assays were performed on the aortic roots as described previously (15, 16). Hearts were perfused with PBS, fixed in 10% phosphate-buffered formalin, embedded in OCT compound, and sectioned with a cryostat at 10 µm thickness. Slides containing the aortic tissue were stained with Oil Red O and hematoxylin and counterstained with light green. Lesions of the proximal aorta were measured in 80 µm intervals. The mean lesion area of six sections was calculated and shown as lesion area (µm2). The atherosclerotic lesions were assessed by en face assays (17).

Statistical analysis
Comparisons between two genotypes were performed using a two-tailed Student's t-test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Perlecan expression in blood vessels
The expression of perlecan within the aorta of apoE mice fed a chow diet differed markedly as a function of disease within the vessel. In normal, nondiseased aortas, perlecan staining was primarily localized to the subendothelial regions (Fig. 1A) . In more advanced lesions, additional staining was found within the fibrous cap that would be expected to have proliferated smooth muscle cells (Fig. 1B). Most remarkably, in advanced lesions with lipid-filled cores, intense staining was within the lipid core (Fig. 1C). Thus, perlecan is a major matrix protein within the lesions.



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  		Fig. 1. Perlecan expression in lesions of atherosclerosis varies with lesion severity. A: In normal aorta, perlecan was distributed in the subendothelial regions. B,C: Perlecan expression increased markedly in advanced lesions, in the fibrous cap as well as in the plaque core.

 
Quantitative real-time PCR for the aortic perlecan gene
To determine whether heterozygous perlecan knockout mice have an alteration of perlecan expression, the aortic content of perlecan mRNA was compared with that of control mice. A shown in Fig. 2 , deletion of one allele reduced perlecan expression.



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  		Fig. 2. Perlecan expression in aortas by quantitative real-time PCR. Aortas from heterozygous LDL receptor (LDLr)-deficient mice and heterozygous perlecan (Prl) mice in the heterozygous LDL receptor-deficient background were used for real-time PCR. Aortas from three mice from each group were pooled for RNA per set. The data shown are averages of two sets. Values are expressed as mean ± SEM.

 
Lipids in perlecan heterozygous knockout mice
Because lipoprotein uptake by the liver is thought to be mediated, in part, by "capture" by proteoglycans, we assessed whether the loss of perlecan would alter plasma lipoproteins. Table 1 shows plasma and lipoprotein lipids of wild-type and perlecan heterozygous mice eating chow and a Paigen diet. Both strains of mice had identical levels of plasma cholesterol and triglyceride, VLDL, LDL, and HDL. This was confirmed by FPLC analysis (data not shown). When these mice were placed on a Paigen diet, both the controls and perlecan heterozygous mice had a similar increase in plasma apoB-containing lipoproteins. However, loss of perlecan did not affect lipids.


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  		TABLE 1. Lipid profiles of wild-type and heterozygous perlecan-deficient mice fed chow and Paigen diets

 
Lipoprotein uptake via receptors might have obscured any uptake as a result of liver or peripheral tissue heparan sulfate proteoglycan-mediated processes. Therefore, we next examined lipids and lipoproteins in apoE0 and apoE0/perlecan heterozygous mice. As expected, compared with wild-type mice, apoE deficiency led to marked increases of cholesterol and triglyceride at 12 weeks of age (Table 2). However, perlecan deficiency did not significantly alter plasma cholesterol, which was 420 ± 105 mg/dl for apoE0 mice and 359 ± 114 mg/dl for apoE0/perlecan heterozygous mice. A second group of mice was maintained on this diet for 24 weeks (Table 2). Again, the lipids and lipoproteins were not different. Therefore, perlecan deficiency did not alter either plasma or lipoprotein lipids in the apoE0 background.


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  		TABLE 2. Lipid profiles of heterozygous perlecan-deficient mice in the apoE0 background

 
Perlecan-deficient mice were then crossed with LDL receptor knockouts. Because our primary objective was to study atherosclerosis, we created a colony of heterozygous LDL receptor knockouts and fed them the Paigen diet as reported by van Haperen et al. (18). Male LDL receptor heterozygous (LDL+/–) and perlecan-deficient LDL+/– mice were begun on a Paigen diet at 4 weeks of age and maintained on this diet for 16 weeks. Plasma cholesterol in these mice averaged 579 ± 33 and 595 ± 32 mg/dl in LDL+/– and perlecan-deficient/LDL receptor-deficient mice, respectively (Table 3).


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  		TABLE 3. Lipid profiles of heterozygous perlecan-deficient mice in the LDL receptor heterozygous background on the Paigen diet for 16 weeks

 
Atherosclerosis in control and perlecan heterozygous apoE0 mice
In the chow-fed apoE knockout mice, both early lesions (12 weeks) and later lesions (24 weeks) were studied. In 12 week old male mice, perlecan deficiency led to a dramatic and significant reduction in lesion size, which averaged 23,961 µm2 in controls and 7,796 µm2 in perlecan heterozygous animals (P = 0.02) (Table 4). Lesion sizes for individual animals are shown in Fig. 3A , graphed on a semi-log scale. Lack of perlecan led to a >70% reduction in lesion size. This amount of atherosclerosis was too small to allow for en face quantification. Lesion size in female mice is also shown in Table 4 and Fig. 3A. Although a trend toward reduced lesions was noted in the perlecan heterozygous females, this was not significant.


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  		TABLE 4. Atherosclerotic lesions of heterozygous perlecan-deficient mice in the apoE0 background

 


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  		Fig. 3. Effects of heterozygous perlecan deficiency on atherosclerotic lesions. Heterozygous perlecan deficiency was crossed into the apoE knockout background. Male and female chow-fed mice were assessed for lipids and atherosclerosis after 12 weeks (A) and 24 weeks (B). The data obtained from sections of the aortic root are shown on a log scale. P < 0.05.

 
After 24 weeks, male perlecan heterozygous mice still had, on average, less atherosclerosis, 121,961 µm2 in controls and 89,167 µm2 in perlecan heterozygous animals, but this difference was not significant (Fig. 3B). Female mice had larger lesions, but there was no difference with the presence of a perlecan knockout allele. En face assays also showed no difference in lesion area with perlecan deficiency, 2.8 ± 2% in apoE0 mice and 1.9 ± 1.2% in apoE0/perlecan heterozygous mice (average ± SD, P = 0.2).

Atherosclerosis in heterozygous LDL receptor-deficient mice
It has been hypothesized that the interaction of lipoproteins with proteoglycans might differ in mice that express apoE (19), a stronger proteoglycan binding protein than apoB. For this reason, we assessed whether a similar degree of atherosclerosis in heterozygous LDL receptor knockout mice would still show the effects of perlecan deficiency on atherosclerosis. For this reason, male mice were studied at 20 weeks. As shown in Fig. 4 , perlecan deficiency did not alter atherosclerosis in this model. The average lesion areas in heterozygous LDL receptor-deficient and heterozygous perlecan-deficient mice in the LDL receptor heterozygous background are shown in Table 5.



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  		Fig. 4. Atherosclerosis in LDL receptor (LDLr) heterozygous knockout mice. Perlecan (Prl) heterozygous knockout mice were bred with LDL receptor knockout mice. The offspring, all with a heterozygous deficiency of LDL receptor, were fed a high-fat and cholesterol/cholic acid-containing diet (Paigen) for 16 weeks, and atherosclerotic lesion size at the aortic root was quantified.

 

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  		TABLE 5. Atherosclerotic lesions of heterozygous perlecan-deficient mice in the LDL receptor heterozygous background

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Crossing perlecan heterozygous mice into an atherosclerotic background tested the hypothetical role for heparan sulfate proteoglycans in atherogenesis. Our data show the following. 1) Although perlecan is primarily found in the subendothelial matrix in normal vessels, it is found in core regions of advanced atherosclerotic lesions. 2) Despite a possible role of perlecan in the removal of lipoproteins from the circulation, a heterozygous deletion of perlecan did not alter plasma lipoprotein profiles. 3) Young perlecan heterozygous knockout/apoE0 male mice had reduced atherosclerosis. A similar trend occurred in females. However, older mice and heterozygous LDL receptor-deficient mice had no difference in lesion size.

Endothelial cells produce a number of heparan sulfate proteoglycans when assessed in cultured cells. These include syndecans, which are a component of the cell membrane (20). Perlecan is the major heparan sulfate proteoglycan within the subendothelial matrix; some perlecan is also found associated with the apical side of the cells. Cultured smooth muscle cells express and secrete perlecan (14). Our immunohistological data suggest that both cells express perlecan in vivo, but at different times and under different stimuli. In normal vessels, perlecan was prominently found within the subendothelial matrix. However, with the development of lesions, perlecan staining was decreased in the subendothelial region. In humans, this may result in the decrease in arterial heparan sulfate proteoglycans reported with atherosclerosis (21). The reasons for this decrease might be altered perlecan expression or an increase in its degradation. The latter might result from the actions of heparanase, which is secreted by endothelial cells in response to atherogenic stimuli (22).

Kunjathoor et al. (23) have demonstrated that the major proteoglycans detected in murine atherosclerosis are perlecan and biglycan. Perlecan was present extensively in the lesions of apoE-deficient and LDL receptor-deficient mice. Perlecan was also detected in intermediate and advanced lesions of hypercholesterolemic nonhuman primates and in cultures of medial smooth muscle cells from human atherosclerotic tissue. Our data comparing early and advanced lesions confirm their observations. Like others, we also found perlecan staining surrounding the lipid core (24). Moreover, we found remarkable amounts of perlecan in very advanced lesions containing necrotic lipid cores. Because these regions are distant from endothelial cells, we speculate that either smooth muscle cells or macrophages are the source of this perlecan. Because macrophages do not appear to express perlecan in great quantities (25), either smooth muscle cells or some other cells are the likely origin of most perlecan in mouse atherosclerotic lesions.

We had anticipated that perlecan deficiency would result in a defect in lipoprotein removal from the bloodstream, similar to that found in some diabetic models (26). However neither fasting nor postprandial lipemia differed between control and perlecan heterozygous mice. In fact, the rationale for the use of apoE0 mice was, in part, to allow us to assess the effect of perlecan deficiency on the removal of remnant lipoproteins. We hypothesized that the apoB-48-containing lipoproteins in these mice were unable to interact with either the LDL receptor or the LDL receptor-related protein and relied on heparan sulfate proteoglycan binding for removal. However, partial loss of perlecan was not physiologically significant. Perhaps the apoE-deficient lipoproteins were unable to bind to heparan sulfate proteoglycans, and therefore, perlecan deficiency had no effect.

To test some of these hypotheses, we performed a study in heterozygous LDL receptor knockout mice fed an atherogenic diet. These mice have sufficient hypercholesterolemia to develop atherosclerotic lesions, as noted by others (18); however, perlecan deficiency did not alter the lipoprotein profiles. Using heterozygous LDL receptor knockout mice, we attempted to create lesions that were similar in size to those of the 12 week old male apoE0 mice. Although the lesions were somewhat larger, perlecan deficiency did not alter the lesion size. Perhaps these lesions in the cholic acid-fed mice were more inflammatory and, hence, less affected by a gene deletion that would alter lipoprotein retention. Alternatively, the lesions studied might have been too advanced to find differences. Finally, the pathogenesis of lesions might differ in these two models as a result of the presence of apoE.

Although perlecan was a likely candidate to have affected atherosclerosis progression, the heterozygous mutation could have been expected to increase or decrease lesions. A central role for lipoprotein accumulation attributable to its binding to matrix molecules within the arterial walls was proposed almost 50 years ago by Page (1). The "infiltrative" theory of atherosclerosis suggested that plasma cholesterol-containing lipoproteins accumulate in vessels either because they are present in greater concentrations or that matrix is altered to increase the propensity for the lipoproteins to be retained within the artery. A refinement of this theory termed the "response to retention" suggested that proteoglycans are the matrix component that "traps" atherogenic lipoproteins (27). However, the biochemical evidence supporting an important role for lipoprotein-proteoglycan complexes has been questioned (28). Non-apoE-containing lipoproteins have relatively weak affinity for proteoglycans in physiological ionic conditions. This has led us (28, 29) and others (30) to suggest that lipoprotein-proteoglycan interaction requires an intermediary molecule such as lipoprotein lipase. The other lipoprotein-associating molecule that would be expected to increase lipoprotein-proteoglycan interaction, apoE, is antiatherosclerotic.

Our studies show that perlecan deficiency leads to less atherosclerosis. This was found in early, but not late, lesions of apoE0 mice. Most notable is the comparison of our data with those of Skalen et al. (19), who studied atherosclerosis in mice with an apoB mutation that decreases proteoglycan affinity. Like these authors, we found that later lesions were no longer significantly different from those of controls. In addition, like Skalen et al. (19), we failed to find a major difference in atherosclerosis when perlecan deficiency was assessed in the heterozygous LDL-deficient background. These authors postulated that apoE-containing LDL, found in mice but not in humans, has greater affinity for proteoglycans. Hence, the effects of alterations in apoB structure, and perhaps the amount of vessel wall perlecan, might be less evident in LDL receptor knockout mice.

We conclude that perlecan is a major component of advanced atherosclerotic lesions in the mouse. A heterozygous deficiency of perlecan led to reduced atherosclerosis in apoE0 mice. This effect was found in young males without advanced lesions. Although it is possible that perlecan deficiency alone reduced atherosclerosis as a result of reduced lipoprotein retention, the complexity of the process and the multiple biological actions of perlecan do not allow one to make that conclusion with certainty.


   ACKNOWLEDGMENTS
 
This research was funded by Grants HL-62301 and HL-56984 (SCOR) from the National Heart, Blood, and Lung Institute.

Manuscript received January 21, 2004 and in revised form June 2, 2004. and in re-revised form July 8, 2004.


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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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