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Short Communications |
Enhances Atherosclerosis in Apolipoprotein E-/- Mice
From the Gill Heart Institute, Atherosclerosis Research Group, Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky
| Abstract |
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(IFN-
) has been implied in the
atherogenic process. To determine whether exogenously administered
IFN-
exerts an effect on the development of atherosclerosis,
we intraperitoneally administered either recombinant IFN-
(100 U/g
body weight) or phosphate buffered saline daily for 30 days to
atherosclerosis-susceptible apolipoprotein E-/- mice (16-week-old
male mice, n = 11 per group) fed a normal
diet. Atherosclerotic lesion size was quantified in the ascending
aorta. The number of T lymphocytes and major histocompatibility complex
(MHC) class II-positive cells within lesions were also quantified in
this region. IFN-
administration reduced serum cholesterol
concentrations by 15% (P = 0.02). For both
groups, the majority of cholesterol was present in very low
density lipoproteins, which were modestly reduced in mice
receiving IFN-
. Despite the decrease in serum cholesterol
concentrations, IFN-
injections significantly increased
lesion size twofold compared to controls (119,980 ±
18,536 vs. 59,396 ± 20,017
µm2; P = 0.038). IFN-
also
significantly increased the mean number of T lymphocytes (19 ± 4
vs. 7 ± 1 cells; P = 0.03) and
MHC class II-positive cells (10 ± 3 vs. 3 ±
1 cells; P = 0.04) within lesions. These data lend
further support to a pro-atherogenic role of IFN-
.
| Introduction |
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|
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One of the prominent cytokines secreted
during activation of specific subtypes of T lymphocytes is
interferon-
(IFN-
). Both protein and mRNA for this cytokine have
been detected in atherosclerotic lesions from humans7,12
and mice.13
IFN-
has a range of biological properties
in cultured cells that could influence development of atherosclerotic
lesions. These include effects on class A scavenger
receptors,12,14,15
low density lipoprotein
receptor-related protein,16
15-lipoxygenase,17
lipoprotein oxidation,18
lipoprotein lipase,19
extracellular matrix
deposition,20
increased expression of vascular cellular
adhesion molecule-1,21
and smooth muscle cell
proliferation.22
This complex array of in vitro
effects makes it difficult to predict the effects of IFN-
on the
development of atherosclerotic lesions.
The most direct evidence for a role of IFN-
in the development of
atherosclerosis is based on a study of mice deficient in IFN-
receptors.23
Mice with compound deficiencies of
apolipoprotein E (apoE) and the IFN-
receptor developed less
atherosclerosis than mice with only an apoE deficiency.23
In addition to the decrease in atherosclerosis, IFN-
receptor-deficient mice developed lesions with decreased
cellularity and lipid accumulation, but increased collagen deposition.
There is the potential for differing responses in mice deficient for
the cytokine rather than the receptor.24
However, to date
there have been no studies that compare the effects of these
deficiencies on the development of atherosclerosis.
In the present study, we determined whether exogenous administration of
IFN-
would influence the development of atherosclerosis in apoE-/-
mice. We demonstrated that administration of recombinant IFN-
increases lesion size in apoE-/- mice and is accompanied by a
significant increase in the number of lesion-associated T lymphocytes
and major histocompatibility complex (MHC) class II-positive cells.
Therefore, these data provide further support to the hypothesis that
IFN-
is a potent atherogenic cytokine.
| Materials and Methods |
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|
|
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Lyophilized recombinant mouse IFN-
(catalog no. 485-MI, R&D
Systems, Minneapolis, MN) was reconstituted in solution A, sterile
phosphate buffered saline (PBS) containing 0.1% bovine serum albumin,
to prepare a stock concentration of 50 µg/ml (200,000 U/ml) as
recommended by the manufacturer.
Animals
Twenty-two 16-week-old male apoE-/- mice, progeny from five
breeding pairs of apoE-/- mice, were originally obtained from The
Jackson Laboratory (Bar Harbor, ME). This strain of mouse had been
back-crossed 10 times to the C57BL/6 strain. Equal numbers of siblings
from the five litters were divided into two groups of 11 mice. One
group of mice received daily peritoneal injections of IFN-
(100 U/g
body weight) diluted in PBS, while the second group received daily
injections of solution A (to control for the presence of bovine serum
albumin), also diluted in PBS. Daily injections were performed for 30
days, during which time the mice were kept on a normal laboratory diet.
Mice were housed in a pathogen-free facility and exposed to a 12-hour
light and dark cycle. All procedures involving animals were approved by
the University of Kentucky Institutional Animal Care and Use
Committee.
Blood Collection
At the end of the injection period, mice were anesthetized by metafane inhalation. Terminal blood samples were collected by puncture of the right ventricle. Blood was allowed to clot at room temperature for 30 minutes, then centrifuged at 1000 x g for 25 minutes at 4°C. Mice were perfused with PBS via a cannula placed in the left ventricle while the perfusate drained from a severed right atrium. The hearts were separated from the aortas at the base, embedded in OCT, and frozen at -20°C.
Plasma Cholesterol and Lipoprotein Profiles
Individual serum total cholesterol concentrations were determined using a commercially available colorimetric assay (Wako Bioproducts, Richmond, VA), following a slight modification of the manufacturers instructions to allow for quantification using a 96-well microtiter plate format. Serum samples (50 µl) from each mouse were used to determine individual lipoprotein cholesterol distributions evaluated after fractionation by size exclusion chromatography (Biological Workstation, Bio-Rad, Richmond, CA) using a Superose 6 column (Pharmacia LKB Biotechnology, Uppsala, Sweden). Fractions were collected and cholesterol concentrations determined using the total cholesterol assay (Wako).
Lesion Analysis
Atherosclerotic size in the ascending aorta was determined from 4 Oil Red O-stained serial sections, cut 8 µm thick and collected 80 µm apart, starting at the region where the aortic sinus becomes the ascending aorta. Lesion area, defined by Oil Red O staining of the intima, was determined using Image-Pro software (Media Cybernetics, Silver Spring, MD) on files that were created using a Spot camera (Diagnostic Instruments, Sterling Heights, MI). The mean lesion area derived from the 4 serial sections was taken as the average lesion size for each animal.
Immunocytochemical and Histological Characterization of Atherosclerotic Lesions
Immunocytochemistry and extracellular matrix staining were performed as described previously,25 on serial sections of the ascending aorta adjacent to those stained with Oil Red O. The following monoclonal antibodies were used for immunostaining: an anti-mouse Thy1.2 antibody (01011D, 7 µg/ml; PharMingen, Los Angeles, CA); and an anti-mouse MHC II antibody (LS-004-SN, 1:5 dilution; Biosource International, Camarillo, CA). An immunoperoxidase assay (Vectastain Elite ABC kit, Vector Laboratories, Burlingame, CA) was used to detect the primary antibody after addition of a biotinylated anti-rat IgG absorbed against mouse serum. Immunoreactivity was visualized using the chromagen 3-amino-9-ethyl carbazole (Biomeda Corp., Foster City, CA). Endogenous tissue peroxidase was removed before immunostaining by exposure of tissue to H2O2. The possibility of nonspecific staining was addressed by staining serial sections as described above, but in the absence of a primary antibody. Extracellular elastin and collagen were visualized with Verhoeffs and Gomori trichrome stain, respectively.
Statistics
Data analyses were performed using SigmaStat 2.03 software (SPSS
Inc., Chicago, IL). For each parameter, the mean and standard error of
the mean (SEM) were calculated. Statistical analysis between PBS- and
IFN-
injected groups was by Students t-test after
testing that the data complied with the constraints of parametric
analysis. P values <0.05 were considered statistically
significant.
| Results |
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|
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into ApoE-/- Mice Reduced Serum Cholesterol
Concentrations
ApoE-deficient mice develop hyperlipidemia and atherosclerosis
when fed a normal laboratory diet.26,27
In this study,
apoE-/- mice on a normal diet developed moderate
hypercholesterolemia, the extent of which decreased significantly by
15% in mice receiving IFN-
compared to mice injected with PBS only
(278 ± 11 vs. 324 ± 15 mg/dl, respectively;
P = 0.02). Size exclusion chromatography, performed on
individual serum samples, showed that for both groups, the majority of
cholesterol was present in the very low density lipoprotein (VLDL)
fraction, and that this fraction was modestly reduced in the group
receiving IFN-
(Figure 1)
.
|
Significantly Increased
Atherosclerosis, Lesion T Lymphocytes, and Lesion MHC Class
II-Positive Cells
Segments of heart tissue spanning the aortic sinus and ascending
aorta were embedded in OCT, serially sectioned and analyzed for
atherosclerotic lesion size, and lesion number of both T-lymphocytes
and MHC class II-positive cells. Daily administration of IFN-
caused
a significant twofold increase in lesion size compared to control
groups (119,980 ± 18,536 vs. 59,396 ± 20,017
µm2, respectively; P = 0.038;
Figure 2A
). Accompanying this increase in
lesion size, addition of exogenous IFN-
also significantly increased
the number of both T lymphocytes (19 ± 4 vs. 7 ±
1 mean cell number; P = 0.03; Figure 2B
). and MHC class II-positive cells (10 ± 3 vs.
3 ± 1 mean cell number; P = 0.04; Figure 2C
) in
atherosclerotic lesions. A representative example of the immunostained
T lymphocytes is shown in Figure 3, E and F
. Based on examination of immunostained tissue sections, the bulk of
lesions was composed of lipid-laden macrophages (Figure 3, C and D)
.
Gomori trichrome staining demonstrated that there was little collagen
present within the lipid-laden foam cell, and a modest accumulation
within macrophages that were not so lipid-engorged (Figure 3, G and H)
.
There was a tendency toward more areas of no lipid-laden foam cells in
IFN-
-treated mice.
|
|
| Discussion |
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|
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mRNA in atherosclerotic lesions
has led to speculation about its role as the mediator of T
lymphocyte-induced changes of the disease process. The most direct
evidence for a role of this cytokine in the disease is the reduction in
the size of atherosclerotic lesions that occurs in apoE-/- mice that
are also deficient in IFN-
receptors.23
The lesions
generated in the absence of IFN-
receptors had marked differences in
both cell and extracellular matrix composition. In this study, we
looked at the effect of exogenous IFN-
on lesion development in
apoE-/- mice that were IFN-
receptor-competent. In agreement with
the conclusion of Gupta et al23
that IFN-
is a
pro-atherogenic cytokine, we observed a significant increase in lesion
size of mice receiving exogenous IFN-
. However, though we noted
increases in the number of T lymphocytes and MHC class II-positive
cells, we did not observe any grossly observable changes in both
cellular and extracellular matrix composition of the lesions.
Furthermore, the increase in atherosclerosis occurred even though there
was a modest reduction in plasma cholesterol concentrations
attributable to a decrease in VLDL cholesterol.
Radiolabeled IFN-
is rapidly removed from the plasma of mice
following intravenous injection, with sequestration mainly in the liver
and kidney.28
Because absorption into the blood of solutes
injected i.p. is usually rapid, it may be expected that parenterally
administered IFN-
would also be rapidly removed from the plasma
compartment. However, in the present study, this apparent transient
presence in plasma was sufficient to have effects on both plasma
cholesterol concentrations and atherosclerosis.
The finding of IFN-
injections decreasing plasma cholesterol are in
agreement with the increases observed in IFN-
receptor-deficient
animals.23
Since IFN-
has no effect of low density
lipoprotein receptor activity29
and decreases low density
lipoprotein receptor-related protein,16
the
reduction in cholesterol concentrations may not be due to enhanced
hepatic removal. Therefore, although this was a consistent effect, the
mechanism underlying this response is not apparent. As described above,
there are numerous biological effects of IFN-
that could have direct
relevance to both foam cell formation and the process of fatty streak
development. Further study will be needed to determine whether the
effect of IFN-
is due to a concerted effect or whether one
mechanism is dominant.
Previously, IFN-
has been parenterally administered to demonstrate
the effects on smooth muscle proliferation in rats.30
Contrary to the effect we observed on atherosclerotic lesions,
administration of IFN-
to rats with carotid artery injury led to an
attenuation of intimal thickening. However, subcutaneously administered
IFN-
increased arteriosclerosis in transplanted arteries in
mice.31
In our study, the lesions formed in these young
apoE-/- mice fed a normal diet were almost exclusively lipid-laden
macrophages. Although we observed a pro-atherogenic effect under these
conditions, further work may be needed to define whether IFN-
exerts
a similar pro-atherogenic effect at other stages in the maturation of
atherosclerotic lesions in which there would be a more complex cellular
and biochemical composition.
Using an experimental protocol which we mimicked in our current study,
Lee et al32
recently demonstrated that daily injections of
interleukin-12 (IL-12) will significantly increase lesion development
in apoE-/- mice. Given that IL-12 is a potent inducer of IFN-
expression,33
and that addition of exogenous
IL-1232
and now IFN-
will promote atherosclerosis in
apoE-/- mice, IL-12 and IFN-
may belong to a common pathway
involved in promoting lesion development through induction of an
inflammatory reaction.
| Acknowledgements |
|---|
| Footnotes |
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S. C. W. was a recipient of a Heart and Stroke Foundation of Canada Fellowship and currently holds an American Heart Association (Ohio Valley Affiliate) Fellowship.
Accepted for publication September 8, 2000.
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M. Hagihara, A. Higuchi, N. Tamura, Y. Ueda, K. Hirabayashi, Y. Ikeda, S. Kato, S. Sakamoto, T. Hotta, S. Handa, et al. Platelets, after Exposure to a High Shear Stress, Induce IL-10-Producing, Mature Dendritic Cells In Vitro J. Immunol., May 1, 2004; 172(9): 5297 - 5303. [Abstract] [Full Text] [PDF] |
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Z. Chen, M. Sakuma, A. C. Zago, X. Zhang, C. Shi, L. Leng, Y. Mizue, R. Bucala, and D. I. Simon Evidence for a Role of Macrophage Migration Inhibitory Factor in Vascular Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 709 - 714. [Abstract] [Full Text] [PDF] |
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D. M. Wuttge, X. Zhou, Y. Sheikine, D. Wagsater, V. Stemme, U. Hedin, S. Stemme, G. K. Hansson, and A. Sirsjo CXCL16/SR-PSOX Is an Interferon-{gamma}-Regulated Chemokine and Scavenger Receptor Expressed in Atherosclerotic Lesions Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 750 - 755. [Abstract] [Full Text] [PDF] |
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M. S. Burnett, S. Durrani, E. Stabile, M. Saji, C. W. Lee, T. D. Kinnaird, E. P. Hoffman, and S. E. Epstein Murine Cytomegalovirus Infection Increases Aortic Expression of Proatherosclerotic Genes Circulation, February 24, 2004; 109(7): 893 - 897. [Abstract] [Full Text] [PDF] |
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A. Gojova, V. Brun, B. Esposito, F. Cottrez, P. Gourdy, P. Ardouin, A. Tedgui, Z. Mallat, and H. Groux Specific abrogation of transforming growth factor-{beta} signaling in T cells alters atherosclerotic lesion size and composition in mice Blood, December 1, 2003; 102(12): 4052 - 4058. [Abstract] [Full Text] [PDF] |
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O. J de Boer, A. E Becker, and A. C van der Wal T lymphocytes in atherogenesis--functional aspects and antigenic repertoire Cardiovasc Res, October 15, 2003; 60(1): 78 - 86. [Full Text] [PDF] |
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B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF] |
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Z. Mallat, A. Gojova, V. Brun, B. Esposito, N. Fournier, F. Cottrez, A. Tedgui, and H. Groux Induction of a Regulatory T Cell Type 1 Response Reduces the Development of Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, September 9, 2003; 108(10): 1232 - 1237. [Abstract] [Full Text] [PDF] |
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C. A. Reardon, L. Blachowicz, J. Lukens, M. Nissenbaum, and G. S. Getz Genetic Background Selectively Influences Innominate Artery Atherosclerosis: Immune System Deficiency as a Probe Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1449 - 1454. [Abstract] [Full Text] [PDF] |
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M. Benagiano, A. Azzurri, A. Ciervo, A. Amedei, C. Tamburini, M. Ferrari, J. L. Telford, C. T. Baldari, S. Romagnani, A. Cassone, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions PNAS, May 27, 2003; 100(11): 6658 - 6663. [Abstract] [Full Text] [PDF] |
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K. Y. Stokes, E. C. Clanton, K. P. Clements, and D. N. Granger Role of Interferon-{gamma} in Hypercholesterolemia-Induced Leukocyte-Endothelial Cell Adhesion Circulation, April 29, 2003; 107(16): 2140 - 2145. [Abstract] [Full Text] [PDF] |
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C. Buono, C. E. Come, G. Stavrakis, G. F. Maguire, P. W. Connelly, and A. H. Lichtman Influence of Interferon-{gamma} on the Extent and Phenotype of Diet-Induced Atherosclerosis in the LDLR-Deficient Mouse Arterioscler. Thromb. Vasc. Biol., March 1, 2003; 23(3): 454 - 460. [Abstract] [Full Text] [PDF] |
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N. R. Webb, M. A. Bostrom, S. J. Szilvassy, D. R. van der Westhuyzen, A. Daugherty, and F. C. de Beer Macrophage-Expressed Group IIA Secretory Phospholipase A2 Increases Atherosclerotic Lesion Formation in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 263 - 268. [Abstract] [Full Text] [PDF] |
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N. Kalinina, A. Agrotis, E. Tararak, Y. Antropova, P. Kanellakis, O. Ilyinskaya, M. T. Quinn, V. Smirnov, and A. Bobik Cytochrome b558-Dependent NAD(P)H Oxidase-Phox Units in Smooth Muscle and Macrophages of Atherosclerotic Lesions Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2037 - 2043. [Abstract] [Full Text] [PDF] |
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A. S. Major, S. Fazio, and M. F. Linton B-Lymphocyte Deficiency Increases Atherosclerosis in LDL Receptor-Null Mice Arterioscler. Thromb. Vasc. Biol., November 1, 2002; 22(11): 1892 - 1898. [Abstract] [Full Text] [PDF] |
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K. Kozaki, W. E. Kaminski, J. Tang, S. Hollenbach, P. Lindahl, C. Sullivan, J.-C. Yu, K. Abe, P. J. Martin, R. Ross, et al. Blockade of Platelet-Derived Growth Factor or Its Receptors Transiently Delays but Does Not Prevent Fibrous Cap Formation in ApoE Null Mice Am. J. Pathol., October 1, 2002; 161(4): 1395 - 1407. [Abstract] [Full Text] [PDF] |
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF] |
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U. Schonbeck, G. K. Sukhova, N. Gerdes, and P. Libby TH2 Predominant Immune Responses Prevail in Human Abdominal Aortic Aneurysm Am. J. Pathol., August 1, 2002; 161(2): 499 - 506. [Abstract] [Full Text] [PDF] |
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A. Daugherty and D. L. Rateri T Lymphocytes in Atherosclerosis: The Yin-Yang of Th1 and Th2 Influence on Lesion Formation Circ. Res., May 31, 2002; 90(10): 1039 - 1040. [Full Text] [PDF] |
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L. J. Pinderski, M. P. Fischbein, G. Subbanagounder, M. C. Fishbein, N. Kubo, H. Cheroutre, L. K. Curtiss, J. A. Berliner, and W. A. Boisvert Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor-Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes Circ. Res., May 31, 2002; 90(10): 1064 - 1071. [Abstract] [Full Text] [PDF] |
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S. Agrawal, M. L. Agarwal, M. Chatterjee-Kishore, G. R. Stark, and G. M. Chisolm Stat1-Dependent, p53-Independent Expression of p21waf1 Modulates Oxysterol-Induced Apoptosis Mol. Cell. Biol., April 1, 2002; 22(7): 1981 - 1992. [Abstract] [Full Text] [PDF] |
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G. K. Hansson The B Cell: A Good Guy in Vascular Disease? Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 523 - 524. [Full Text] [PDF] |
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P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF] |
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V. L. King, S. J. Szilvassy, and A. Daugherty Interleukin-4 Deficiency Decreases Atherosclerotic Lesion Formation in a Site-Specific Manner in Female LDL Receptor-/- Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 456 - 461. [Abstract] [Full Text] [PDF] |
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B. R. Kwak, S. Myit, F. Mulhaupt, N. Veillard, N. Rufer, E. Roosnek, and F. Mach PPAR{gamma} but not PPAR{alpha} Ligands Are Potent Repressors of Major Histocompatibility Complex Class II Induction in Atheroma-Associated Cells Circ. Res., February 22, 2002; 90(3): 356 - 362. [Abstract] [Full Text] [PDF] |
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S. C. Whitman, P. Ravisankar, and A. Daugherty Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E-/- Mice Through Release of Interferon-{gamma} Circ. Res., February 8, 2002; 90 (2): e34 - e38. [Abstract] [Full Text] [PDF] |
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N. Gerdes, G. K. Sukhova, P. Libby, R. S. Reynolds, J. L. Young, and U. Schonbeck Expression of Interleukin (IL)-18 and Functional IL-18 Receptor on Human Vascular Endothelial Cells, Smooth Muscle Cells, and Macrophages: Implications for Atherogenesis J. Exp. Med., January 22, 2002; 195(2): 245 - 257. [Abstract] [Full Text] [PDF] |
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G. K. Hansson Immune Mechanisms in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1876 - 1890. [Abstract] [Full Text] [PDF] |
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S. C. Whitman, P. Ravisankar, and A. Daugherty Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E-/- Mice Through Release of Interferon-{gamma} Circ. Res., February 8, 2002; 90 (2): e34 - e38. [Abstract] [Full Text] [PDF] |
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B. R. Kwak, S. Myit, F. Mulhaupt, N. Veillard, N. Rufer, E. Roosnek, and F. Mach PPAR{gamma} but not PPAR{alpha} Ligands Are Potent Repressors of Major Histocompatibility Complex Class II Induction in Atheroma-Associated Cells Circ. Res., February 22, 2002; 90(3): 356 - 362. [Abstract] [Full Text] [PDF] |
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P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF] |
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