Atherosclerosis and Lipoproteins |
From the Center for Molecular and Vascular Biology (B.D.G., M.L, M.L, D.C., P.H.), University of Leuven, Leuven, Belgium; and INSERM U321 (D.S., L.L.G., E.N.), Lipoproteins and Atherogenesis, Institut Fédératif Muscle Coeur et Vaisseaux, Hôpital Pitié-Salpêtrière and UFR Médecine Sud (Université Pierre et Marie Curie), Paris, France.
Correspondence to Paul Holvoet, PhD, Center for Molecular and Vascular Biology, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be
| Abstract |
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Key Words: HDL gene transfer platelet-activating factor acetylhydrolase paraoxonase
| Introduction |
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The antiatherogenic potential of HDL may also be related to its anti-inflammatory and antioxidative properties, which are mediated by several mechanisms. First, reactive oxidized lipids may be transferred from LDL to HDL,8 which may inhibit the propagation of an oxidation cascade in LDL. HDL has indeed been shown to be the predominant carrier of cholesterol ester hydroperoxides in humans.9 After transfer to HDL, cholesterol ester hydroperoxides are taken up much more efficiently by hepatocytes than are native cholesterol esters,10 11 providing a link between the antioxidative properties of HDL and reverse cholesterol transport.
Second, several HDL-associated enzymes may protect LDL against oxidative modification. LDL oxidation has been shown to induce fragmentation of the sn-2 residue of phospholipids,12 generating oxidized phospholipids with potent proinflammatory effects. Platelet-activating factor acetylhydrolase (PAF-AH; EC.3.1.1.47), which in humans is associated with both LDL and HDL,13 hydrolyzes not only the ester bond in the sn-2 position of PAF to release acetate but has also been shown to hydrolyze peroxidized fatty acids of phospholipids.12 PAF-AH pretreatment of oxidized phospholipids blocked the mitogenic activity toward smooth muscle cells in culture, which could also be abolished by a PAF receptor antagonist.14 Treatment of mildly oxidized LDL with PAF-AH inhibited the ability of mildly oxidized LDL to induce endothelial cells to bind monocytes and to produce monocyte chemotactic protein-1.15 Lecithin-cholesterol acyltransferase, which circulates mostly in association with HDL, has also been demonstrated to hydrolyze truncated phosphatidylcholines generated during lipoprotein oxidation.16
Paraoxonase (PON1, aryldialkylphosphatase; EC.3.1.8.1) is a glycoprotein of 43-kDa molecular weight, which circulates in an HDL subfraction that also contains apo A-I and clusterin.17 PON1 is a member of a multigene family located on human chromosome 7, which contains 2 additional PON1-like genes, designated PON2 and PON3. PON1 has long been known for its capacity to detoxify the organophosphate-type pesticides and nerve gases by hydrolysis.18 However, the demonstration that formation of total lipid peroxides and thiobarbituric acidreactive substances, as a result of copper ioncatalyzed LDL oxidation, was reduced by purified PON1 has highlighted a new, physiologically important role for this enzyme.19 PON1 has been shown to have peroxidase activity and to hydrolyze lipid peroxides in oxidized lipoproteins with a preference for cholesteryl linoleate.20 Gene targeting of PON1 has generated unequivocal evidence for the role of PON1 in the protection against LDL oxidation and against the progression of atherosclerosis. HDL isolated from PON1-knockout mice was unable to prevent LDL oxidation, and PON1-knockout mice were more susceptible to diet-induced atherosclerosis than were their wild-type littermates.21
Because oxidized LDLs may promote monocyte adhesion and foam cell generation, induce smooth muscle cell proliferation and migration, and enhance platelet adhesion and aggregation, oxidation of LDL in the arterial wall is thought to be an initiator of atherosclerosis.22 23 Enhancement of the antioxidative and anti-inflammatory potential of HDL induced by elevated levels of apo A-I may therefore be mechanistically linked to the inhibition of atherosclerosis in human apo A-Itransgenic animals3 4 5 6 and the inhibition of injury-induced neointima formation.24 25 26 Therefore, we evaluated the effect of human apo A-I overexpression by transgenesis or adenovirus-mediated gene transfer in C57BL/6 and C57BL/6 apo E-/- mice on PAF-AH activity and on the arylesterase and paraoxonase activity of PON1.
| Methods |
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Animal Experiments
All experimental procedures in animals were performed in
accordance with protocols approved by the Institutional Animal Care and
Research Advisory Committee. All mice used in this study were female
and 3 to 5 months of age. Apo E-/-
mice28 were backcrossed for 10 generations into the
C57BL/6J background and had 99.9% C57BL/6J background. Human apo
A-Itransgenic mice used in this study were originally described by
Rubin et al.29 The human apo A-Itransgenic apo
E-/- mice used here have been described
before.30 Mice were fed normal chow ad libitum. Virus
administration was performed by tail vein injection. Different doses of
recombinant adenovirus were administered in a final volume of 300
µL.
Isolation of Lipoproteins by Gel Filtration
Mice were killed after an overnight fast, and maximal blood
volume was obtained by puncture of the inferior vena cava.
To obtain plasma, anticoagulation was performed with 0.1 volume of 4%
trisodium citrate. Separation of lipoproteins by gel filtration in a
fast pressure liquid chromatography system (Waters
Associates) was performed as described previously.26 For
gel filtration of serum, an isotonic saline buffer (10 mmol/L
Tris-HCl [pH 7.4], 137 mmol/L NaCl, 5 mmol/L KCl, 1
mmol/L CaCl2, and 1 mmol/L
MgCl2) was used.
A pool of fractions 10 to 17 containing VLDL-, IDL-, and LDL-size lipoproteins was used to determine PAF-AH and arylesterase activity of non-HDLsize lipoproteins. Similarly, fractions 18 to 25 and 26 to 33, corresponding to large-size and small-size HDL lipoproteins, respectively, were pooled, and PAF-AH and arylesterase activities were determined on these pools.
For determination of cholesterol levels, cholesterol of fractions obtained after gel filtration was extracted with methanol/chloroform (2:1, vol/vol). Esterified and unesterified cholesterol levels were quantified by high-performance liquid chromatography on a reversed-phase column (Zorbax ODS, Du Pont de Nemours) essentially as described by Vercaemst et al.31
Human Apo A-I ELISA
Human apo A-I levels were determined by sandwich ELISA. In
brief, polystyrene microtiter plates (Costar) were coated with a rabbit
anti-human apo A-I polyclonal antibody. Diluted plasma samples
(1:25 000, 1:50 000, 1:100 000, and 1:200 000) were added to the
wells for 2 hours. After being washed, a 1:15 000 dilution of the
murine monoclonal antibody
A4H4A7
conjugated with peroxidase was placed on the wells for 2 hours.
Peroxidase reaction was performed by adding
H2O2 and
o-phenylenediamine. Finally, absorbance was
measured at 492 nm.
Determination of PAF-AH Activity
Hexadecyl PAF, obtained as a powder from Sigma Chemical Co, was
dissolved at a final concentration of 20 mmol/L in ethanol (80%
vol/vol). This solution was mixed with
1-O-hexadecyl-2-[3H-acetyl]-sn-glycero-3-phosphocholine
(10 Ci/mmol, DuPontNew England Nuclear), dried under a stream of
N2, and redissolved in a solution containing
fatty acidfree bovine serum albumin (0.25% wt/vol in saline)
to obtain a 50 µmol/L [3H-acetyl]PAF
solution. AH activity was measured by the trichloroacetic acid
precipitation procedure as previously described.32 In
brief, the pH of the HEPES-EDTA (2 mmol/L) buffer was adjusted to
7.4, and routine assays were performed for 10 minutes at 37°C in a
total volume of 100 µL. Plasma was diluted 2000-fold and lipoprotein
fractions were diluted 10-fold in HEPES buffer before addition of 10
µL of [3H-acetyl]PAF (50 µmol/L;
specific activity,
6000 disintegrations per minute per
nanomole).
Determination of Arylesterase and Paraoxonase Activity of
PON1
Arylesterase activity was measured by using phenylacetate as a
substrate.33 Initial rates of hydrolysis were determined
spectrophotometrically at 270 nm in a Power Wave 200 microplate
scanning spectrophotometer (Bio-Tek Instruments). The assays were
performed in a final volume of 250 µL containing 1 mmol/L
phenylacetate and 2 mmol/L CaCl2 in 20
mmol/L Tris-HCl buffer, pH 8.0, in the presence of 0.1 µL of mouse
serum or 10 µL of lipoprotein fraction for 5 minutes. The
extinction coefficient at 270 nm for the reaction was 1307
mol/L-1 · cm-1 for
1 micromole of phenylacetate hydrolyzed per minute.
The rate of hydrolysis of paraoxon was assessed by measuring liberation of p-nitrophenol at 405 nm at 25°C.34 The assays were performed in a final volume of 250 µL containing 5.5 mmol/L paraoxon and 2 mmol/L CaCl2 in 100 mmol/L Tris-HCl buffer, pH 8.0, in the presence of 2 to 4 µL of mouse serum for 4 minutes. The extinction coefficient at 405 nm for the reaction was 17 000 mol/L-1 · cm-1 for 1 nanomole of p-nitrophenol converted per minute.
Evaluation of an Acute-Phase Response and Cytokine
Production After Adenoviral Gene Transfer
High-resolution electrophoresis of serum was carried out by
using Hydragel 15 HR (Sebia Benelux) according to the instructions of
the manufacturer. Albumin,
2-globulins, and complement component
C3 were quantified by densitometric scanning.
Plasma levels of interleukin-1 (IL-1ß) and interleukin-6 (IL-6) were
determined by using the Quantikine M immunoassays (R&D Systems
Europe).
Statistical Analysis
All data are expressed as mean±SEM. Significance of differences
in cholesterol values were assessed by a 2-tailed,
unpaired, alternate Welch t test with the
INSTAT V2.05a statistical program (Graph Pad
Software). Comparison of PAF-AH activity, arylesterase activity, and
paraoxonase activity was performed by the nonparametric
Mann-Whitney U test. The correlation between arylesterase
and paraoxonase activity of PON1 and the correlation between PAF-AH
activity and human apo A-I was calculated by using the
nonparametric Spearman rank correlation in the
INSTAT V2.05a statistical program. A two-sided
P value of <0.05 was considered statistically
significant.
| Results |
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PAF-AH Activity in C57BL/6 and C57BL/6 Apo E-/-
Mice
PAF-AH activity in C57BL/6 control mice (n=16), in C57BL/6 mice 6
days after gene transfer with 109 pfu of
Adt-PA adenovirus (n=12) or of AdapoA-I
adenovirus (n=11), and in human apo A-I C57BL/6 transgenic mice (n=5)
is shown in Figure
IA. PAF-AH activity
was not significantly different in C57BL/6 control mice and C57BL/6
mice treated with Adt-PA control virus. PAF-AH activity
increased 2.0-fold (P<0.0001) after AdapoA-I
transfer and was 4.2-fold (P<0.0001) elevated in human apo
A-Itransgenic mice. PAF-AH activity was 2.1-fold
(P=0.0009) higher in human apo A-I C57BL/6 transgenic mice
than in AdapoA-Itreated mice.
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PAF-AH activity in apo E-/- control mice
(n=9), in apo E-/- mice 6 days after gene
transfer with 109 pfu of Adt-PA
adenovirus (n=11) or AdapoA-I adenovirus (n=12), and in
human apo A-I apo E-/- transgenic mice (n=4) is
shown in Figure
IB. PAF-AH activity was 1.6-fold
(P=0.008) lower in apo E-/- than in
C57BL/6 mice. No significant alteration of PAF-AH activity was observed
after Adt-PA transfer in apo E-/-
mice. PAF-AH activity increased 1.8-fold (P=0.0024) after
AdapoA-I gene transfer and was 2.1-fold (P=0.010)
elevated in human apo A-I apo E-/- transgenic
mice.
To investigate the association between human apo A-I overexpression and
increase in PAF-AH activity in C57BL/6 apo E-/-
mice, 3 different doses of AdapoA-I adenovirus
(5x108, 109, and
2x109 pfu; n=4 for each dose) were administered,
and PAF-AH activity was determined 6 days after gene transfer. The
correlation between human apo A-I plasma levels and PAF-AH activity was
0.92 (P<0.0001; Figure
II).
To investigate the kinetics of increased PAF-AH activity after adenovirus-mediated gene transfer, 2x109 pfu of AdapoA-I was administered to C57Bl/6 apo E-/- mice, and PAF-AH activity was determined at days 3, 6, 14, and 21 after gene transfer. Figures IIIA and IIIB illustrate human apo A-I plasma levels and plasma PAF-AH activity, respectively. PAF-AH activity was increased 2.5-fold at day 3 (P<0.0001), 3.3-fold at day 6 (P<0.0001), 1.7-fold at day 14 (P<0.0001), and 1.4-fold at day 21 (P=0.01).
Lipoprotein Distribution of PAF-AH Activity
Figure
IV illustrates the
lipoprotein distribution of PAF-AH activity in C57BL/6 (A) and apo
E-/- (B) mice, respectively. In C57BL/6 control
mice, 83% of PAF-AH activity was recovered in large-size HDL particles
and 13% in small-size HDL particles. This distribution was similar
after Adt-PA gene transfer. PAF-AH activity in large-size
HDL and small-size HDL particles increased 1.8-fold
(P=0.0005) and 3.7-fold (P=0.0005), respectively,
after gene transfer with 109 pfu of
AdapoA-I. PAF-AH activity in large-size HDL and small-size
HDL particles of human apo A-Itransgenic mice was 2.1-fold
(P=0.040) and 18-fold (P=0.0015) higher,
respectively, than in control mice. The activity associated with
small-size HDL particles contributed 25% and 56% of total
lipoprotein-associated activity in AdapoA-Itreated C57BL/6
mice and human apo A-Itransgenic mice, respectively.
In C57BL/6 apoE-/-control mice, 52% of PAF-AH activity was present in large-size HDL and 41% in small-size HDL. PAF-AH activity increased 2.2-fold (P=0.014) in large-size HDL after AdapoA-I gene transfer, whereas no significant change occurred in small-size HDL. PAF-AH activity in large-size HDL and small-size HDL of human apo A-Itransgenic mice was 2.1-fold (P<0.05) and 2.1-fold (P=0.0028) higher, respectively, than in control mice.
Arylesterase and Paraoxonase Activity of PON1 in C57BL/6 and
C57BL/6 Apo E-/- Mice
Arylesterase and paraoxonase activities of PON1 in C57BL/6 control
mice (n=7), in C57BL/6 mice 6 days after gene transfer with
109 pfu of Adt-PA adenovirus (n=4) or
AdapoA-I adenovirus (n=4), and in human apo A-I C57BL/6
transgenic mice (n=9) are shown in Figures
VA and VB, respectively.
Arylesterase activity decreased 1.8-fold (P=0.0061) after
both Adt-PA and AdapoA-I gene transfer and was
1.5-fold (P=0.0003) higher in human apo A-Itransgenic mice
than in C57BL/6 control mice. Paraoxonase activity decreased 2.1-fold
(P=0.0061) and 2.3-fold (P=0.0061) after
Adt-PA and AdapoA-I gene transfer, respectively,
and was 1.7-fold (P=0.0012) higher in human apo
A-Itransgenic mice than in C57BL/6 mice. Arylesterase and paraoxonase
activities of PON1 were highly correlated (r=0.98,
P<0.0001).
Figures VC and VD illustrate the arylesterase and paraoxonase activity, respectively, of PON1 in C57BL/6 apoE-/- control mice (n=4), in C57BL/6 apo E-/- mice 6 days after gene transfer with 109 pfu of Adt-PA virus (n=5) or AdapoA-I virus (n=4), and in human apo A-I C57BL/6 apoE-/- transgenic mice (n=4). Paraoxonase activity was not determined after Adt-PA transfer in apoE-/- mice. Arylesterase and paraoxonase activities were 1.4-fold (P=0.042) and 2.0-fold (P=0.012) lower, respectively, in apo E-/- mice than in C57BL/6 mice. No significant alteration of arylesterase activity was observed after Adt-PA or AdapoA-I gene transfer. Compared with apoE-/- control mice, arylesterase and paraoxonase activity increased 1.8-fold (P=0.029) and 2.5-fold (P=0.029), respectively, in human apo A-I apoE-/- transgenic mice. Arylesterase and paraoxonase activities of PON1 were highly correlated (r=0.90, P=0.0002).
Figure
IIIC illustrates the time course of arylesterase
activity after gene transfer with 2x109 pfu of
AdapoA-I in C57BL/6 apo E-/- mice.
Compared with baseline, arylesterase was 1.2-fold lower at day 3
(P<0.05), 1.8-fold lower at day 6 (P<0.0001),
2.2-fold lower at day 14 (P<0.0001), and was not
significantly different at day 21.
Lipoprotein Distribution of Arylesterase Activity
Figure
VI illustrates the
lipoprotein distribution of arylesterase activity in C57BL/6 (A) and
apo E-/- mice (B), respectively. Activities
were determined on fractions obtained after gel filtration of pooled
serum samples. In C57BL/6 control mice, 91% of arylesterase activity
was present in large-size HDL particles and 8% in small-size HDL
particles. The 1.8-fold decrease in serum arylesterase activity after
Adt-PA and AdapoA-I gene transfer corresponded
to a 1.5-fold and a 2.2-fold decrease, respectively, of
arylesterase activity associated with large-size HDL particles. The
1.5-fold higher serum arylesterase in human apo A-Itransgenic mice
corresponded to a 1.7-fold increase of activity associated with
large-size HDL particles.
In apo E-/- mice, 88% of arylesterase activity was present in large-size HDL particles and 6% in small-size HDL particles. The 1.8-fold increase in serum arylesterase activity in human apo A-Itransgenic apo E-/- mice corresponded to a 1.5-fold increase of arylesterase activity in large-size HDL particles.
Plasma Cytokines and Acute-Phase Response Proteins After
Gene Transfer
IL-1ß concentration in plasma was below detection (7.5 pg/mL) in
control C57BL/6 mice (n=4) and was 70±44 pg/mL 6 days after gene
transfer with AdapoA-I in C57BL/6 mice. IL-6 was below
detection (15.6 pg/mL) in both control mice and 6 days after gene
transfer with AdapoA-I. High-resolution electrophoresis of
serum proteins in C57BL/6 mice at baseline (n=9) and 6 days after human
apo A-I gene transfer (n=6) showed a 15% (P=0.0004)
decrease of albumin, a 48% (P=0.0008) increase of
2-globulins, and a 13% (P=0.040)
increase of the complement component C3.
| Discussion |
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PAF-AH was predominantly associated with HDL, and only a minor fraction of the activity was associated with non-HDL. In contrast, approximately two thirds of PAF-AH activity in humans is associated with LDL and one third with HDL.12 Recently, Stafforini et al35 demonstrated that amino acids 205, 115, and 116 are important for the binding of human PAF-AH to LDL and that the carboxyl terminus of apo B-100 plays a key role in the association of PAF-AH with LDL. When residues 115 and 116 of human PAF-AH were introduced into murine PAF-AH, the mutant murine PAF-AH associated with LDL. Therefore, both the amino acid sequence of murine PAF-AH and low levels of apo B-100 in mice may contribute to the predominant association of murine PAF-AH with HDL.
Human apo A-I overexpression in C57BL/6 transgenic mice and in mice treated with the human apo A-I adenovirus was associated with a relative increase in PAF-AH activity in small HDL compared with large HDL. These small, human apo A-Icontaining HDL particles isolated by gel filtration may correspond to the very high density lipoprotein-1 subfraction (VHDL-1) isolated by isopycnic density-gradient ultracentrifugation, which has previously been shown to preferentially bind PAF-AH.32 In contrast to C57BL/6 control mice, a significant amount of PAF-AH activity in control apo E-/- mice was associated with small HDL. It is possible that the absence of apo E in apo E-/- mice affects murine PAF-AH distribution in large- and small-size HDL particles. Previously, it has been shown that human PAF-AH associates exclusively with LDL and HDL containing apo E.13 Also, the significantly reduced amount of murine apo A-I in HDL of apo E-/- control mice36 may affect PAF-AH distribution and may cause lower PAF-AH activity associated with HDL in these mice.
In contrast to PAF-AH, PON1 was predominantly associated with
large-size HDL particles, and only a small fraction of activity was in
small-size HDL particles. The association of PON1 with HDL is mediated
through the binding of its retained hydrophobic N-terminal
leader sequence to HDL phospholipids and does not involve a direct
association with apo A-I,37 which may contribute to
the observed differences between the distribution of PAF-AH and PON1.
Arylesterase and paraoxonase activities increased in human apo
A-Itransgenic C57BL/6 and apo E-/- mice but
decreased after human apo A-I gene transfer in C57BL/6 and apo
E-/- mice. This discrepancy may be explained by
the production of inflammatory cytokines in the liver
after gene transfer with the first-generation
E1-deleted adenoviral vectors. Paraoxonase
activity and PON1 mRNA levels in the liver have indeed been
shown to decrease after tumor necrosis factor-
and IL-1
administration in Syrian hamsters.38 The presence of
detectable Il-1ß in plasma after gene transfer, the decrease of the
negative acute-phase response protein albumin, and the increase
of
2-globulins and complement component
C3 indicate that cytokine
production was induced in the liver after gene transfer. Thus,
high liver concentrations of cytokines after gene transfer may
have resulted in decreased PON1 expression. It remains to be
investigated whether human apo A-I overexpression induced by gene
transfer with a new-generation, nontoxic adenoviral vector can increase
paraoxonase activity in C57BL/6 and apo E-/-
mice.
Previously, Castellani et al39 reported that the PAF-AH and arylesterase activity is similar in HDL isolated by ultracentrifugation from the plasma of C57BL/6 mice and human apo A-Itransgenic mice, at least when data are normalized for total HDL protein. The PAF-AH and arylesterase activity in HDL isolated by gel filtration in the present study represents the total activity, which was not normalized for HDL protein. Thus, our data in C57BL/6 and human apo A-Itransgenic mice are in accordance with those of Castellani et al.39 The present study also demonstrates that PAF-AH and arylesterase/paraoxonase activity in C57BL/6 apo E-/- mice was significantly lower than in C57BL/6 mice. Decreased paraoxonase activity in apo E-/- mice has been previously described by Hayek et al,40 although the extent of decrease (1.4-fold) was lower than in this study (2.0-fold). This may be related to differences in genetic background or in age of the mice.
The increase in PAF-AH and paraoxonase activity in human apo A-I C57BL/6 apo E-/- transgenic mice to levels equal to or above those of C57BL/6 mice may significantly contribute to the inhibition of progression of atherosclerosis4 5 by restoring an effective anti-inflammatory and antioxidant activity of HDL. Theilmeier et al41 recently demonstrated that human apo A-I transgenesis is associated with reduced oxidative stress in apo E-/- mice, reduced ß-VLDLtriggered endothelial cytosolic Ca2+ signaling through PAF-like bioactivity, and diminished ex vivo leukocyte adhesion. Furthermore, adenoviral gene transfer of PAF-AH reduced in vivo macrophage homing in the absence of increased HDL cholesterol, indicating the potential physiological significance of elevated PAF-AH activity.
In conclusion, this study provides evidence that overexpression of human apo A-I increases HDL-associated PAF-AH activity. In contrast to higher paraoxonase activity in human apo A-Itransgenic mice, paraoxonase activity after human apo A-I gene transfer decreases, probably due to cytokine-mediated inhibition of PON1 expression. Increased levels of these HDL-associated enzymes may improve the anti-inflammatory and antioxidative potential of HDL and may directly contribute to the protection conferred by HDL against atherothrombosis.
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| Acknowledgments |
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Received May 25, 2000; accepted June 14, 2000.
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