Original Contributions |
From the University of Adelaide, Department of Medicine, Royal Adelaide Hospital (D.T.A., M.A.C., P.J.B.), the Cardiovascular Investigation Unit, Royal Adelaide Hospital (K.A.-R.), and the Hanson Centre for Cancer Research, Department of Human Immunology, IMVS (M.A.V., J.R.G.), Adelaide, South Australia, Australia.
Correspondence to Professor Philip J. Barter MBBS, PhD, Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia 5000.
| Abstract |
|---|
|
|
|---|
(TNF-
). HDLs
collected from a number of different human subjects all inhibited
VCAM-1 expression in a concentration-dependent manner, although the
extent of inhibition varied widely between subjects. The
inhibitory activities of the HDL2 and
HDL3 subfractions isolated from individual subjects also
differed. Whether equated for concentrations of apolipoprotein (apo)
A-I or cholesterol, the inhibitory activity of
HDL3 was superior to that of HDL2. This
difference remained apparent even when the HDL subfractions were
present only during preincubations with the HUVECs and were removed
before activation by TNF-
. To determine whether the
inhibitory effect of HDL3 was influenced by
apolipoprotein composition, preparations of HDL3 were
modified by replacing all of their apo A-I with apo A-II. This change
in apolipoprotein composition had no effect on the ability of the
HDL3 to inhibit endothelial VCAM-1
expression. Thus, it has been shown that different preparations of HDLs
differ markedly in their abilities to inhibit VCAM-1 expression in
cytokine-activated HUVECs. The mechanism underlying the
differences remains to be determined.
Key Words: endothelial cells vascular cell adhesion molecule-1 HDL HDL subfractions atherosclerosis
| Introduction |
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Adhesion of monocytes to the vascular endothelium is one of the earliest events in atherogenesis.5 This adhesion is mediated by adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1, and E-selectin,6 all of which are rapidly synthesized by endothelial cells in response to stimulation by cytokines.7 The expression of endothelial cell VCAM-1 coincides with the development of early foam cell lesions in hypercholesterolemic rabbits,8 whereas VCAM-1, intercellular adhesion molecule-1, and E-selectin have all been detected in the arterial endothelium over existing atheromatous plaques.9 The concentration of soluble VCAM-1 has been reported to be elevated in the plasma of patients with atherosclerosis.10
The current study addresses the ability of HDLs to inhibit cytokine-induced expression of VCAM-1 in endothelial cells. Specifically, it seeks to determine whether HDLs from different subjects or HDLs of differing size and composition also differ in terms of their ability to inhibit adhesion molecule expression.
| Methods |
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HDL particle size distribution was assessed by electrophoresis on 3% to 40% nondenaturing polyacrylamide gradient gels (Gradipore).11 Concentrations of apolipoproteins and lipid constituents in the HDLs were determined as described previously.12
Isolation of HDL2 and HDL3 Proteins
and Lipids
HDL2 and HDL3 were
isolated as described above and delipidated as
described.13 The protein constituents were
resuspended in PBS and stored at 4°C. The lipids were extracted by
the method of Folch et al14 and resuspended in
PBS before being sonicated under N2 by the method
of Sparks et al15 at 51°C. The resuspended
apolipoproteins and the sonicated lipid preparations were stored at
4°C and were used within 1 week.
Preparation of HDL3 Containing Apo A-II Only (A-II
HDL3)
The apo A-I in HDL3 was displaced with
lipid-free apo A-II as described previously.16 In
brief, HDL3s were isolated by
ultracentrifugation as described above. Lipid-free apo
A-II was added to the HDL3 at an apo A-II to apo
A-I molar ratio of 2:1. As a control, another aliquot of
HDL3 was supplemented with PBS in place of apo
A-II. Both samples were maintained at room temperature for 30 minutes
and then reisolated as the supernatant after
ultracentrifugation at 1.21 g/mL. The samples were
dialyzed against 3x 1 L of endotoxin-free PBS before use.
Preparation of Discoidal Reconstituted HDLs
Discoidal reconstituted HDLs (rHDLs) containing apo A-I and
1-palmitoyl-2-oleyl-phosphatidylcholine (POPC) were prepared by the
cholate dialysis method described by Matz and
Jonas.17
Human Umbilical Vein Endothelial Cells
(HUVECs)
HUVECs were isolated as described
previously.18 Cells were cultured on
gelatin-coated culture flasks in medium M199 with Earle's salts (Trace
Biosciences) supplemented with 20% FCS (Commonwealth Serum
Laboratories), 20 mmol/L HEPES, 2 mmol/L glutamine, 1
mmol/L sodium pyruvate, nonessential amino acids, penicillin,
streptomycin, 20 mg/mL endothelial growth supplement
(Collaborative Research), and 20 mg/mL heparin (Sigma Chemical Co).
Incubation Conditions
Confluent preparations of passage 3, 4, or 5 HUVECs were
incubated for 1 hour in the presence of the various preparations of
total HDL, HDL subfractions, and A-II HDL3. Tumor
necrosis factor-
(TNF-
) (100 U/mL) was then added to the culture
medium, and 4.5 hours later the cell surface expression of VCAM-1 was
measured by flow cytometry analysis.
Flow Cytometry Analysis
Levels of cell surface expression of VCAM-1 were measured as
described previously.4 In brief, the cells were
first washed with FACS wash (RPMI 1640, containing 10 mmol/L
HEPES, 0.02% sodium azide, and 2.5% FCS). HUVECs were then
incubated with mouse monoclonal antibody to VCAM-1 (51-10C9) for 30
minutes at 4°C and then washed again with FACS wash. Binding of the
primary antibody was detected by incubation with FITC-conjugated
secondary antibody [Immunotech FITC-conjugated
F(ab)2 fragment goat (mouse IgG)] for 30 minutes
at 4°C. After being washed with PBS, the cells were harvested by
trypsinization. FACS wash was added to neutralize the trypsin. The
cells were centrifuged and the cell pellet resuspended in FACS
fixative (PBS containing 2% glucose, 0.02% sodium azide, and
2.5% formaldehyde). The expression of VCAM-1 was measured as
fluorescence intensity by using a Coulter Epics Profile II flow
cytometer. Each sample counted 10 000 cells. Controls included
preparations without the primary antibody and an isotype-matched,
nonrelevant antibody.
Statistical Analyses
The data obtained in this study are expressed as mean±SEM.
Students' t test for paired samples was used to determine
whether differences between values were significant. Statistical
significance was set at P<0.05.
| Results |
|---|
|
|
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|
|
Having found intersubject variations in the HDL-mediated inhibition of endothelial cell VCAM-1 expression, studies were next conducted to investigate whether different HDL subfractions also differed in their inhibitory activity. In the first of these we compared HDL2 and HDL3.
Comparison of the Inhibition of VCAM-1 Expression by
HDL2 and HDL3
HDL2 (1.07<d<1.12 g/mL) and
HDL3 (1.13<d<1.21 g/mL) were
isolated from each of 5 subjects. Completeness of the separation of
each subfraction from the other was confirmed by nondenaturing
polyacrylamide gradient gel electrophoresis (Figure 3
). The compositions of the
HDL2 and HDL3 are shown in
Table 1
. As has been reported
elsewhere,19 HDL3s are
enriched with apo A-II but depleted of cholesteryl esters, unesterified
cholesterol, and triglyceride relative to
HDL2.
|
|
The HDL2 and HDL3 were
added to HUVECs at apo A-I concentrations of 2, 4, and 8 µmol/L.
Both HDL subfractions inhibited the TNF-
induced VCAM-1 expression
in a concentration-dependent fashion (Figure 4
). However, at all concentrations of apo
A-I, the inhibition mediated by HDL3 was greater
than that of HDL2 (Figure 4A
). The differences at
4 and 8 µmol/L apo A-I were statistically significant. At 4
µmol/L apo A-I, the inhibition of VCAM-1 expression by
HDL2 and HDL3 was
39.8±5.7% and 58.6±5.4%, respectively (P<0.05). This
difference was even greater at 8 µmol/L apo A-I, with
HDL2 and HDL3 inhibiting
VCAM-1 expression by 46.2±8.0% and 71.4±5.8% respectively
(P<0.05). When the inhibitory activities of
HDL2 and HDL3 were compared
in terms of their total cholesterol concentrations, the
HDL3 subfraction was still superior (Figure 4B
).
|
Effect of Removing HDL2 and HDL3 Prior to
Adding TNF-
To determine whether the difference between
HDL2 and HDL3 was dependent
on the HDL subfractions' being physically present at the time the
TNF-
was added, studies were conducted with cells that had been
preincubated for 2 hours with each of the HDL subfractions. The HDL
subfractions were then removed before TNF-
was added. Before the
TNF-
was added, the cells were washed twice with fresh medium to
ensure maximal removal of the HDLs. With this technique, >95% of the
added HDL (expressed as apo A-I) was accounted for in the removed
medium.
Despite removal of the HDLs before the addition of TNF-
, expression
of VCAM-1 was still inhibited in a concentration-dependent manner
(Figure 5
). Furthermore, the superior
inhibitory activity of HDL3
persisted. At concentrations of apo A-I of 2, 4, and 8 µmol/L
during preincubation, the subsequent inhibition of TNF-
induced
VCAM-1 expression was, respectively, 14%, 32%, and 46% in the case
of HDL2 and 31%, 50%, and 60% in the case of
HDL3.
|
Effects of Isolated HDL2 and HDL3
Apolipoproteins and Lipids on VCAM-1 Expression
To investigate the possibility that the differences between
HDL2 and HDL3 may have
reflected differences in their protein or lipid constituents, their
apolipoproteins and lipids were isolated and their effects on
TNF-
induced VCAM-1 expression determined. In marked contrast to
the intact HDL subfractions, neither the apolipoproteins (Figure 6A
) nor sonicated preparations of the
lipids (Figure 6B
) from either subfraction had any significant
inhibitory activity. Similarly, when HUVECs were incubated
with purified apo A-I (up to 24 µmol/L) in the absence of lipid
or with sonicated, small, unilamellar vesicles prepared with POPC (up
to 3.2 mmol/L) in the absence of apolipoproteins, there was no
inhibition of the TNF-
induced expression of VCAM-1 (result not
shown). When, however, apo A-I and POPC were reconstituted into
discoidal rHDLs, the resulting complexes promoted a
concentration-dependent inhibition of VCAM-1 expression comparable to
that seen with native HDLs (Figure 7
).
|
|
Effect of Apolipoprotein Composition on the Inhibition of VCAM-1
Expression by HDL3
HDL3 includes 2 main apolipoprotein-specific
subpopulations: 1 containing apo A-I only (A-I
HDL3) and the other containing both apo A-I and
apo A-II (A-I/A-II HDL3).20
To determine whether changing the apolipoprotein composition of
HDL3 impacts the ability of these lipoproteins to
inhibit VCAM-1 expression, preparations of HDL3
were modified by replacing all of their apo A-I with apo A-II to form
(A-II) HDL3. This replacement of apo A-I with apo
A-II increased the size of the HDL3 particles
slightly (from 8.9 to 9.2 nm, Figure 8B
)
but did not change their lipid composition (Table 2
). The modified
HDL3s containing only apo A-II were then compared
with the unmodified particles, which comprised a mixture of (A-I) and
(A-I/A-II) HDL3 (Figure 8A
).
|
|
Both the unmodified HDL3 and (A-II)
HDL3 inhibited the cytokine-induced
expression of VCAM-1 in endothelial cells in a
concentration-dependent fashion (Figure 8A
). When equated for
cholesterol concentration (and thus for HDL particle
concentration), there was no difference in the magnitude of the
inhibition achieved by the 2 preparations.
| Discussion |
|---|
|
|
|---|
The apparent superiority of HDL3 over HDL2 in terms of inhibiting VCAM-1 expression may be a consequence of differences in either the particle size or the composition of the subfractions. It is well known that other functions of HDLs, such as their interaction with lecithin:cholesterol acyltransferase21 and hepatic lipase,22 are influenced by variations in both of these parameters. Other more subtle differences between the HDL subfractions, such as variations in the conformation of their apolipoproteins, may also impact on function by altering the surface exposure of specific apolipoprotein epitopes. It is possible, however, that the superiority of HDL3 as an inhibitor of VCAM-1 is unrelated to any of these differences in size, composition, or structure. Rather, it may be a simple reflection of the fact that when the 2 subfractions are equated for concentrations of either apo A-I or cholesterol, there are more HDL3 particles than HDL2 particles. This issue is being addressed in studies using rHDLs in which the size and composition can be more tightly controlled.
The mechanism by which HDLs inhibit endothelial
cell adhesion molecule expression is uncertain. One possibility relates
to the ability of HDLs to function as antioxidants. The fact that
endothelial cell VCAM-1 expression may be induced by
redox-sensitive transcriptional events23 raises
the possibility that the ability of HDLs to inhibit
endothelial cell adhesion molecule expression may be
secondary to their known capacity to remove any lipid oxidation
products24 that may be generated by TNF-
.
If this were so, it could be argued that the difference between the
inhibitory activities of HDL2 and
HDL3 may reflect their relative abilities to
remove such lipid oxidation products. However, this mechanism was
not consistent with the observation that the
inhibitory activities of the HDL subfractions remained
different even when the HDLs were present only during
preincubations and were removed from the endothelial
cells before the addition of TNF-
(Figure 5
). These preincubation
studies also excluded the possibility that the HDLs may have acted by
interfering with the binding of TNF-
to its cell receptors. Rather,
it appears that HDLs somehow "prime" endothelial
cells to be resistant to the cytokine-induced
expression of VCAM-1.
Insights into which components of HDLs are responsible for the
inhibition of VCAM-1 expression were obtained from the studies with
discoidal rHDLs (Figure 7
). Discoidal complexes containing only apo A-I
and POPC were able to mimic native HDLs in their ability to inhibit
endothelial cell VCAM-1 expression. The fact that
neither lipid-free apoA-I alone nor POPC vesicles that did not contain
apo A-I had inhibitory activity indicated that both
apolipoproteins and lipids are required for the effect. In retrospect,
it was therefore predictable that there was no inhibitory
activity detected in either the delipidated proteins or the extracted
lipids isolated from HDL2 and
HDL3. This negative result frustrated attempts to
determine whether the differing inhibitory activities of
the 2 HDL subfractions resided in their lipid or apolipoprotein
moieties. However, it was possible to show that major changes to the
apolipoprotein composition of HDL3 had little
effect on its ability to inhibit endothelial cell
VCAM-1 expression. This observation is consistent with a recent
report that rHDLs containing apoA-I are comparable to those containing
apoA-II as inhibitors of endothelial cell
VCAM-1 expression,25 although it does not address
the possibility of differences between A-I HDLs and A-I/A-II HDLs, the
2 main apolipoprotein-specific HDL subpopulations in human plasma.
The relationship between the inhibition of endothelial cell adhesion molecule expression and the antiatherogenic properties of HDL subpopulations is not known. This is not a trivial issue, because human and animal studies have suggested that HDL2 may differ from HDL3 and A-I HDLs may differ from A-I/A-II HDLs in terms of their cardioprotective properties. Several reports have concluded that HDL2s are superior to HDL3s,26 27 28 although there have also been conclusions that HDL3 may be the superior antiatherogenic subfraction.29 30 31 The observation that high levels of HDL cholesterol are generally indicative of high levels of HDL2 highlights the importance of HDL2 as a cardioprotective fraction. However, the probability that HDL3 is also cardioprotective is suggested by the fact that an inverse relationship between the concentration of HDL cholesterol and the risk of developing coronary heart disease persists even when the total HDL cholesterol concentration is <1.0 mmol/L and there is no measurable HDL2.
There is also evidence that apolipoprotein composition may be an important determinant of the ability of HDLs to inhibit atherosclerosis. Studies of transgenic animals32 33 34 suggest that A-I HDLs may be superior to both A-I/A-II HDLs and A-II HDLs in their ability to protect against atherosclerosis. However, as with HDL2 and HDL3, the situation in humans is uncertain, with circumstantial evidence both in favor35 and against36 the proposition that A-I HDLs account for most of the ability of HDLs to protect against coronary heart disease. It remains to be determined whether A-I HDLs are also superior to A-I/A-II HDLs in their ability to inhibit endothelial cell adhesion molecule expression and, if so, whether such superiority translates into an enhanced ability to inhibit the development of atherosclerosis.
In conclusion, the ability of HDLs to inhibit the cytokine-induced expression of endothelial cell VCAM-1 has been confirmed and extended by finding marked differences in the inhibitory activities of the 2 major HDL subfractions and in HDL preparations isolated from different human subjects. The mechanism responsible for these differences is not immediately apparent. Future studies designed to investigate whether this inhibition of endothelial cell adhesion molecule expression contributes to the ability of HDLs to inhibit the development of atherosclerosis are awaited with interest.
| Acknowledgments |
|---|
was a generous
gift of Genentech, South San Francisco, Calif. We also thank the staff
of the delivery wards of the Women's and Children's Hospital and
Burnside War Memorial Hospital, Adelaide, for the collection of
umbilical cords. Received July 16, 1997; accepted March 27, 1998.
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P. Kee, D. Caiazza, K.-A. Rye, P.H.R. Barrett, L.A. Morehouse, and P.J. Barter Effect of Inhibiting Cholesteryl Ester Transfer Protein on the Kinetics of High-Density Lipoprotein Cholesteryl Ester Transport in Plasma: In Vivo Studies in Rabbits Arterioscler. Thromb. Vasc. Biol., April 1, 2006; 26(4): 884 - 890. [Abstract] [Full Text] [PDF] |
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G. D. Norata, E. Callegari, M. Marchesi, G. Chiesa, P. Eriksson, and A. L. Catapano High-Density Lipoproteins Induce Transforming Growth Factor-{beta}2 Expression in Endothelial Cells Circulation, May 31, 2005; 111(21): 2805 - 2811. [Abstract] [Full Text] [PDF] |
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G. J. de Grooth, A. H. E. M. Klerkx, E. S. G. Stroes, A. F. H. Stalenhoef, J. J. P. Kastelein, and J. A. Kuivenhoven A review of CETP and its relation to atherosclerosis J. Lipid Res., November 1, 2004; 45(11): 1967 - 1974. [Abstract] [Full Text] [PDF] |
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P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF] |
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C. Wadham, N. Albanese, J. Roberts, L. Wang, C. J. Bagley, J. R. Gamble, K.-A. Rye, P. J. Barter, M. A. Vadas, and P. Xia High-Density Lipoproteins Neutralize C-Reactive Protein Proinflammatory Activity Circulation, May 4, 2004; 109(17): 2116 - 2122. [Abstract] [Full Text] [PDF] |
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A. Kontush, E. C. de Faria, S. Chantepie, and M. J. Chapman Antioxidative Activity of HDL Particle Subspecies Is Impaired in Hyperalphalipoproteinemia: Relevance of Enzymatic and Physicochemical Properties Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 526 - 533. [Abstract] [Full Text] |
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A. Kontush, S. Chantepie, and M. J. Chapman Small, Dense HDL Particles Exert Potent Protection of Atherogenic LDL Against Oxidative Stress Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1881 - 1888. [Abstract] [Full Text] [PDF] |
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L. Calabresi, M. Gomaraschi, and G. Franceschini Endothelial Protection by High-Density Lipoproteins: From Bench to Bedside Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1724 - 1731. [Abstract] [Full Text] [PDF] |
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S.-i. Miura, M. Fujino, Y. Matsuo, A. Kawamura, H. Tanigawa, H. Nishikawa, and K. Saku High Density Lipoprotein-Induced Angiogenesis Requires the Activation of Ras/MAP Kinase in Human Coronary Artery Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 802 - 808. [Abstract] [Full Text] [PDF] |
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Z. Ahmed, S. Babaei, G. F. Maguire, D. Draganov, A. Kuksis, B. N. La Du, and P. W. Connelly Paraoxonase-1 reduces monocyte chemotaxis and adhesion to endothelial cells due to oxidation of palmitoyl, linoleoyl glycerophosphorylcholine Cardiovasc Res, January 1, 2003; 57(1): 225 - 231. [Abstract] [Full Text] [PDF] |
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G. W. COCKERILL, M. C. MCDONALD, H. MOTA-FILIPE, S. CUZZOCREA, N. E. MILLER, and C. THIEMERMANN High density lipoproteins reduce organ injury and organ dysfunction in a rat model of hemorrhagic shock FASEB J, September 1, 2001; 15(11): 1941 - 1952. [Abstract] [Full Text] [PDF] |
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A. Tedgui and Z. Mallat Anti-Inflammatory Mechanisms in the Vascular Wall Circ. Res., May 11, 2001; 88(9): 877 - 887. [Abstract] [Full Text] [PDF] |
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P. W. Baker, K.-A. Rye, J. R. Gamble, M. A. Vadas, and P. J. Barter Phospholipid composition of reconstituted high density lipoproteins influences their ability to inhibit endothelial cell adhesion molecule expression J. Lipid Res., August 1, 2000; 41(8): 1261 - 1267. [Abstract] [Full Text] |
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A. Kawaguchi, Y. Miyao, T. Noguchi, H. Nonogi, M. Yamagishi, K. Miyatake, Y. Kamikubo, K. Kumeda, M. Tsushima, A. Yamamoto, et al. Intravascular Free Tissue Factor Pathway Inhibitor Is Inversely Correlated With HDL Cholesterol and Postheparin Lipoprotein Lipase but Proportional to Apolipoprotein A-II Arterioscler. Thromb. Vasc. Biol., January 1, 2000; 20(1): 251 - 258. [Abstract] [Full Text] [PDF] |
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P. Xia, M. A. Vadas, K.-A. Rye, P. J. Barter, and J. R. Gamble High Density Lipoproteins (HDL) Interrupt the Sphingosine Kinase Signaling Pathway. A POSSIBLE MECHANISM FOR PROTECTION AGAINST ATHEROSCLEROSIS BY HDL J. Biol. Chem., November 12, 1999; 274(46): 33143 - 33147. [Abstract] [Full Text] [PDF] |
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P. W. Baker, K.-A. Rye, J. R. Gamble, M. A. Vadas, and P. J. Barter Ability of reconstituted high density lipoproteins to inhibit cytokine-induced expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells J. Lipid Res., February 1, 1999; 40(2): 345 - 353. [Abstract] [Full Text] |
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D. Sviridov, A. Hoang, W. H. Sawyer, and N. H. Fidge Identification of a Sequence of Apolipoprotein A-I Associated with the Activation of Lecithin:Cholesterol Acyltransferase J. Biol. Chem., June 23, 2000; 275(26): 19707 - 19712. [Abstract] [Full Text] [PDF] |
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