© 1997 American Heart Association, Inc.
Articles |
Deficiency of Inflammatory Cell Adhesion Molecules Protects Against Atherosclerosis in Mice
From the Departments of Molecular and Human Genetics and Medicine, Baylor College of Medicine (M.F.N., E.T.S., D.C.B., A.L.B.), and the Howard Hughes Medical Institute (A.L.B.), Houston, Tex; and Molecular Biology Research, Pharmacia & Upjohn Inc, Kalamazoo, Mich (K.R.M., A.H.L., E.P.M.).
Correspondence to Arthur L. Beaudet, MD, Baylor College of Medicine, One Baylor Plaza, T619, Houston, TX 77030. E-mail abeaudet{at}bcm.tmc.edu
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Abstract |
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Abstract Leukocyte and endothelial cell adhesion molecules (CAMs) are essential for emigration of leukocytes, with the selectins mediating the initial step of leukocyte "rolling" and the ß2-(CD18) integrins and intercellular adhesion molecule-1 (ICAM-1) being important for firm adhesion and emigration. On the basis of evidence for an inflammatory component in the pathogenesis of atherosclerosis, including increased expression of CAMs, cytokines, and growth factors, we tested the hypothesis that decreased expression of inflammatory CAMs would reduce susceptibility to atherosclerosis. Using C57BL/6 mice fed a high-fat diet, we observed a 50% to 75% reduction in atherosclerotic fatty streaks in mice with homozygous mutations for ICAM-1, P-selectin, CD18, both ICAM-1 and CD18, or both ICAM-1 and P-selectin. In contrast to previous evidence of increased expression of CAMs in atherosclerotic lesions, which does not prove a cause-and-effect relationship, these data indicate directly that the level of expression of CAMs can determine the susceptibility to the formation of atherosclerotic fatty streaks. The results suggest that genetic variation at these loci could influence susceptibility to atherosclerosis and that pharmacological reduction of the expression or function of these CAMs might protect against atherosclerosis.
Key Words: atherosclerosis • selectins • intercellular adhesion molecule-1 • ß2-integrins • inflammation
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Introduction |
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Atherosclerosis is a multifactorial process with major genetic predisposing factors. High levels of LDL and low levels of HDL are major risk factors, but there is also substantial evidence that the inflammatory response is a significant variable, with monocytes/macrophages thought to play an important role.1 During an inflammatory response, leukocyte and endothelial CAMs, along with chemoattractant and activator molecules, mediate the emigration of leukocytes. In the systemic circulation, the selectins mediate leukocyte "rolling," the initial step of leukocyte emigration, while the ß2-(CD18) integrins and members of the immunoglobulin adhesion superfamily are important for firm adhesion and subsequent transendothelial migration.2
Previous work has demonstrated increased expression of inflammatory CAMs, such as ICAM-1, VCAM-1, P-selectin, and E-selectin in atherosclerotic lesions,3 4 5 6 7 8 but these data do not distinguish whether the increased expression is a cause or a consequence of the atherosclerotic process. To test the hypothesis that reduced expression of inflammatory CAMs would protect against atherosclerosis, an animal model suitable for long-term study is desirable. Although monoclonal antibodies have been used extensively to block the adhesion of inflammatory CAMs in vivo, genetic manipulation through gene targeting is more suitable for studying chronic disease processes. The availability of mice with mutations for CD18, ICAM-1, and the selectins and the development of mouse models with increased susceptibility to atherosclerosis make it possible to investigate the role of adhesion molecules in the pathogenesis of atherosclerosis. If expression of these inflammatory CAMs is important in the pathogenesis of atherosclerosis, then deficiencies of these molecules should be sufficient to demonstrate an effect under the proposed hypothesis.
C57BL/6 mice fed a high-fat diet develop early lesions of atherosclerosis that are typified by fatty streaks, and this model has been used in many studies, including the demonstration of genetic factors in susceptibility to atherosclerosis among mouse strains.9 10 This model has also been used to document increased atherosclerosis in cholesteryl ester transfer protein–transgenic11 and apolipoprotein(a)-transgenic mice and decreased atherosclerosis in apolipoprotein A-I–transgenic mice.12 Here we report that mice with ICAM-1, P-selectin, CD18, ICAM-1/CD18, or ICAM-1/P-selectin mutations backcrossed onto the C57BL/6 strain show a reduced atherosclerotic lesion size after 20 weeks on a high-fat diet. These findings indicate that leukocyte and endothelial CAMs are directly involved in the pathogenesis of atherosclerosis.
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Methods |
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Mice and Atherosclerosis Experiments
All mutant mice were backcrossed to C57BL/6: 7 generations for P-selectin, 5 generations for ICAM-1, and 7 generations for CD18. Serial serology samples from sentinel animals in the colony were consistently negative for common murine viral pathogens. The study was initiated by changing the diets of mice at 12 weeks of age from autoclaved mouse chow (Ralston Purina 5010), which is low in fat and contains 6% (wt/wt) fat and 0.0275% (wt/wt) cholesterol, to a high-fat, high-cholesterol diet (TD88051, Teklad Premier) containing 15.8% (wt/wt) fat, 1.25% (wt/wt) cholesterol, and 0.5% (wt/wt) sodium cholate. After 20 weeks on the high-fat diet, mice were anesthetized by methoxyfluorane inhalation and killed, and their hearts were removed and fixed (4% phosphate-buffered formaldehyde). During the study period, several mice died after 10 weeks on the high-fat diet, and pathological examination revealed severe fatty liver deposits and gallstones; this group included 3 mice in the C57BL/6 control group, 2 in the ICAM-1 group, 2 in the CD18 group, 4 in the ICAM-1/CD18 group, and 2 in the ICAM-1/P-selectin group.
Evaluation of Atherosclerotic Lesions
Hearts were sectioned as described previously.11 13
In brief, 10-µm cross sections were taken sequentially from just
above the aortic valve along the aorta in the direction of blood flow
until 40 sections had been taken. The sections were processed and the
lesion area of every eighth section was quantified as
described13 ; this report has already validated the use of
selected sections for reliable quantification of lesion area. The sum
of those areas for each mouse was taken as a numerical value that best
characterized the lesion severity of that mouse. Total
cholesterol, HDL, LDL, and VLDL levels were measured as
described previously.11
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Results |
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The CD18,14 ICAM-1,15 and P-selectin16 mutations used in this study result in severe or complete reduction in the expression of the respective proteins. Although there is a low level of residual expression for the CD18 mutation14 and there is evidence for alternatively spliced forms of ICAM-1 expressed in the ICAM-1 mutants,17 substantial impairment of acute inflammatory responses has been demonstrated in these mice. For use of the C57BL/6 mice, it was necessary to backcross the CD18, ICAM-1, and P-selectin mutations onto the C57BL/6 background, and this procedure was done for a minimum of 5 generations before breeding to homozygosity for the CAM mutation. In addition, combined ICAM-1/CD18 and ICAM-1/P-selectin double-mutant mice were obtained by breeding and genotyping.
At 12 weeks of age, female mice that were wild type or homozygous for
the CAM mutations were switched from a normal chow diet to a high-fat,
high-cholesterol diet that was maintained for 20 weeks, at
which time the mice were killed. Hearts were removed, fixed, and
sectioned, and the lesions were quantified essentially as described
previously.11 13 Female mice are significantly more
susceptible to the development of diet-induced disease, and we chose to
use only females to minimize variability and increase the
susceptibility to atherosclerosis. The
Figure
shows the lesion area for
wild-type compared with mutant mice. The mean±SD was 929±520
µm2 for wild-type mice, with a 63% reduction
(347±302 µm2, P<.0001) for the
P-selectin–deficient mice, a 63% reduction (346±225
µm2, P<.0003) for the ICAM-1–deficient mice,
a 47% reduction (497±197 µm2, P<.03)
for the CD18-deficient mice, a 76% reduction (224±156
µm2, P<.0001) for the ICAM-1/CD18–deficient
mice, and a 71% reduction (278±363 µm2,
P<.0002) for the ICAM-1/P-selectin–deficient mice. One
C57BL/6 animal with an extremely elevated lesion area is depicted in
Figure but was not included in statistical calculations. Because the
variation in lesion area was not normally distributed in all
cases,18 mutant groups were compared with wild-type mice
by using the nonparametric Mann-Whitney U
test.
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Plasma lipid profiles were determined for each group of animals
immediately before the high-fat diet was started, after 10 weeks on the
diet, and after 20 weeks on the diet, at which time the mice were
killed (Table). The only
consistent and significant variations involved increased levels
of HDL-C in animals homozygous for the P-selectin deficiency, either
alone or in combination. Before the high-fat diet was started, HDL-C
levels for the P-selectin group were 41% higher (P<.0001)
and for the ICAM-1/P-selectin group 27% higher (P=.0079)
than for wild-type mice. After 20 weeks on the diet, HDL-C levels for
the P-selectin group were 59% higher (P=.0078) and for the
ICAM-1/P-selectin group 80% higher (P=.0038) than for
wild-type mice. Otherwise, the lipid values for the mutant mice were
not significantly different from those of wild-type mice.
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Discussion |
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We interpret the reduction in atherosclerotic lesion area in the mutant mice as direct evidence that reduced expression of leukocyte and endothelial CAMs protect against atherosclerotic lesions. Previous work demonstrating increased expression of ICAM-1, VCAM-1, P-selectin, and E-selectin in atherosclerotic lesions3 4 5 6 7 8 does not prove a cause-and-effect relationship. The genetic approach used in our studies provides more direct evidence for a causal involvement of inflammatory CAMs in the pathogenesis of atherosclerosis. This conclusion is based on the fact that mutations in three different CAM loci mapping to three different chromosomes all lead to significant reductions in lesion area. Although it is known that inbred strains of mice differ in susceptibility to fatty streak formation, with C57BL/6 mice being among the most susceptible and the 129/Sv strain being quite resistant,9 the protection against atherosclerosis cannot be attributed to strain differences. In this regard, the best-defined loci affecting fatty streak formation in the mouse are Ath1, Ath2, and Ath3,10 19 all of which affect HDL-C levels and lesion formation. Consideration of the possibility that the Ath loci might have influenced our results through linkage to the CAM loci eliminates Ath2 and Ath3 from this concern, because they do not map to the same chromosome as any of the genes studied (Ath2 mapping data; personal communication, B. Paigen, 1997). A relationship between the Ath1 and P-selectin mutations is potentially relevant, because both map within 4 to 5 cM on mouse chromosome 1 (Jackson Bioinformatics World Wide Web home page). This raises the possibility that the apparent effect of P-selectin could be mediated by differences between C57BL/6 and 129/Sv mice at the Ath1 locus; the Ath1 genotype of 129/Sv mice is not known. The Ath1 susceptible allele is characterized by a decrease of
50% in HDL-C levels when the mice were placed on the high-fat
diet, and by this criterion, all of the groups showed such a drop and
can be inferred to carry the susceptible allele for
Ath1. On the basis of the HDL-C phenotype, it is
unlikely that the reduced lesion area in P-selectin–deficient mice
could be explained by the Ath1 locus. Neither can differences in blood lipid values explain all of the reduction in fatty streaks seen in the mutant animals. There were no significant differences in lipid values for ICAM-1– or CD18-deficient mice compared with C57BL/6 controls. The HDL-C values for P-selectin–mutant mice were higher than those for C57BL/6 mice; it is uncertain whether this might be a direct effect of the P-selectin mutation or an indirect effect related to a linked locus. Although it is possible that higher levels of HDL-C contribute to the reduction in atherosclerotic lesions in P-selectin–mutant mice, this is unlikely, because there was no correlation between HDL-C levels and lesion area (Spearman rank correlation r=.18), suggesting that the reduction in lesion area was not mediated through increased levels of HDL-C in these animals. The reduction in atherosclerotic lesions in mice with any of three different CAM mutations argues strongly for a direct effect of the expression of CAMs on susceptibility to atherosclerotic lesions.
Atherosclerosis has also been studied in mice with other alterations of immune or inflammatory function. Although there is evidence that T cells may be important in the pathogenesis of atherosclerosis, lesion size was found to be higher in mice with a deficiency of MHC class I molecules20 and in those treated with cyclosporin.21 Osteopetrotic mice have a deficiency of macrophage colony-stimulating factor and severe reductions in the numbers of monocytes and macrophages.22 The osteopetrotic mutation decreases atherosclerosis in apo E–deficient mice.22 The mutations in CAMs would be expected to have broad effects on leukocyte–endothelial cell interactions, but the most relevant effect might be on monocytes/macrophages, given the importance of these cells in the development of fatty streaks, which are the typical lesion of the C57BL/6 mouse on a high-fat diet. The decrease in fatty streaks cannot be explained by a deficiency of monocytes, because the number of circulating monocytes is normal or even higher in the mutants studied (Reference 1616 and unpublished data, M.N. et al, 1997). Monocytes have been shown to express ligands for CD18, ICAM-1, and P-selectin.2
The importance of leukocyte and endothelial CAMs in atherosclerosis and the hypothesis that reduced expression of inflammatory CAMs might have a protective effect have been widely appreciated.1 23 24 Many different risk factors for atherosclerosis could be hypothesized to mediate their effects through altered expression of CAMs, thus affecting the recruitment of monocytes to the endothelium.25 There is evidence that shear stress,26 cigarette smoke,27 an atherogenic diet,5 elevated glucose levels,28 and minimally oxidized LDL29 can contribute to increased expression of leukocyte and endothelial CAMs. Our results are quite consistent with the hypothesis of a direct relationship between CAM expression and lesion formation and indicate that reduced expression of different CAMs leads to reduced lesion area. On the basis of our results, we suggest that expression of inflammatory CAMs may be a particularly pivotal variable in the pathogenesis of atherosclerosis, and it would be of interest to determine whether even half-normal levels of expression in heterozygotes might show an effect on lesion formation. It will also be of interest to study the effect of mutations for CAM in mice with increased susceptibility to atherosclerosis, such as those with a deficiency for apolipoprotein E or the LDL receptor.
Naturally occurring genetic variations in humans could be an important variable in the susceptibility to atherosclerosis. A number of amino acid and DNA polymorphisms30 31 are known in the genes for inflammatory CAMs, and an intensive search would likely identify other variants. One report indicates the association of an allele for an amino acid polymorphism of E-selectin with an increased risk of atherosclerosis.32 33 If expression of inflammatory CAMs is shown to be a major variable in atherosclerosis, development of drugs to reduce the expression or function of these molecules might be of therapeutic value. Although it has been suggested that a systemic reduction of monocyte adhesion would be too dangerous to serve as a therapeutic strategy for atherosclerosis,23 the fact that mice with severe reductions in CAM expression are relatively healthy suggests that an appropriate therapeutic window might exist.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The work was supported by National Institutes of Health grants AI 32177, GM 15483, and AI 01102. We thank William Zoghbi for helpful discussions.
Received August 12, 1996; accepted November 18, 1996.
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References |
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 J. F. Keaney Jr, J. M. Massaro, M. G. Larson, R. S. Vasan, P. W. F. Wilson, I. Lipinska, D. Corey, P. Sutherland, J. A. Vita, and E. J. Benjamin Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study J. Am. Coll. Cardiol., July 7, 2004; 44(1): 168 - 173. [Abstract] [Full Text] [PDF]
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 S. Bro, F. Moeller, C. B. Andersen, K. Olgaard, and L. B. Nielsen Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E-Deficient Mice J. Am. Soc. Nephrol., June 1, 2004; 15(6): 1495 - 1503. [Abstract] [Full Text] [PDF]
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R. C. Braun-Dullaeus, M. J. Mann, D. G. Sedding, S. W. Sherwood, H. E. von der Leyen, and V. J. Dzau Cell Cycle-Dependent Regulation of Smooth Muscle Cell Activation Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 845 - 850. [Abstract] [Full Text]
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H. Koyama, T. Maeno, S. Fukumoto, T. Shoji, T. Yamane, H. Yokoyama, M. Emoto, T. Shoji, H. Tahara, M. Inaba, et al. Platelet P-Selectin Expression Is Associated With Atherosclerotic Wall Thickness in Carotid Artery in Humans Circulation, August 5, 2003; 108(5): 524 - 529. [Abstract] [Full Text] [PDF]
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A. E. May, V. Redecke, S. Gruner, R. Schmidt, S. Massberg, T. Miethke, B. Ryba, C. Prazeres da Costa, A. Schomig, and F.-J. Neumann Recruitment of Chlamydia pneumoniae-Infected Macrophages to the Carotid Artery Wall in Noninfected, Nonatherosclerotic Mice Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 789 - 794. [Abstract] [Full Text] [PDF]
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P. C. Burger and D. D. Wagner Platelet P-selectin facilitates atherosclerotic lesion development Blood, April 1, 2003; 101(7): 2661 - 2666. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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 N.T. Mulvihill, B. Foley, P. Crean, and M. Walsh Prediction of cardiovascular risk using soluble cell adhesion molecules Eur. Heart J., October 2, 2002; 23(20): 1569 - 1574. [Full Text] [PDF]
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I. M. van der Meer, M. P.M. de Maat, M. L. Bots, M. M.B. Breteler, J. Meijer, A. J. Kiliaan, A. Hofman, and J. C.M. Witteman Inflammatory Mediators and Cell Adhesion Molecules as Indicators of Severity of Atherosclerosis: The Rotterdam Study Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 838 - 842. [Abstract] [Full Text] [PDF]
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R. J. Aiello, P.-A. Bourassa, S. Lindsey, W. Weng, A. Freeman, and H. J. Showell Leukotriene B4 Receptor Antagonism Reduces Monocytic Foam Cells in Mice Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 443 - 449. [Abstract] [Full Text] [PDF]
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 C. G. Kevil, R. P. Patel, and D. C. Bullard Essential role of ICAM-1 in mediating monocyte adhesion to aortic endothelial cells Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1442 - C1447. [Abstract] [Full Text] [PDF]
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S. C. Barbaux, S. Blankenberg, H. J. Rupprecht, C. Francomme, C. Bickel, G. Hafner, V. Nicaud, J. Meyer, F. Cambien, and L. Tiret Association Between P-Selectin Gene Polymorphisms and Soluble P-Selectin Levels and Their Relation to Coronary Artery Disease Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1668 - 1673. [Abstract] [Full Text] [PDF]
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J. Husemann, A. Obstfeld, M. Febbraio, T. Kodama, and S. C. Silverstein CD11b/CD18 Mediates Production of Reactive Oxygen Species by Mouse and Human Macrophages Adherent to Matrixes Containing Oxidized LDL Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1301 - 1305. [Abstract] [Full Text] [PDF]
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D. Manka, R. G. Collins, K. Ley, A. L. Beaudet, and I. J. Sarembock Absence of P-Selectin, but Not Intercellular Adhesion Molecule-1, Attenuates Neointimal Growth After Arterial Injury in Apolipoprotein E-Deficient Mice Circulation, February 20, 2001; 103(7): 1000 - 1005. [Abstract] [Full Text] [PDF]
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P. M. Ridker, J. E. Buring, and N. Rifai Soluble P-Selectin and the Risk of Future Cardiovascular Events Circulation, January 30, 2001; 103(4): 491 - 495. [Abstract] [Full Text] [PDF]
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M.-C. Bourdillon, R. N. Poston, C. Covacho, E. Chignier, G. Bricca, and J. L. McGregor ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE-/-/ICAM-1-/-) Fed a Fat or a Chow Diet Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2630 - 2635. [Abstract] [Full Text] [PDF]
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J. W. Knowles and N. Maeda Genetic Modifiers of Atherosclerosis in Mice Arterioscler Thromb Vasc Biol, November 1, 2000; 20(11): 2336 - 2345. [Abstract] [Full Text] [PDF]
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Y. Huo, A. Hafezi-Moghadam, and K. Ley Role of Vascular Cell Adhesion Molecule-1 and Fibronectin Connecting Segment-1 in Monocyte Rolling and Adhesion on Early Atherosclerotic Lesions Circ. Res., July 21, 2000; 87(2): 153 - 159. [Abstract] [Full Text] [PDF]
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N. Kubo, W. A. Boisvert, C. M. Ballantyne, and L. K. Curtiss Leukocyte CD11b expression is not essential for the development of atherosclerosis in mice J. Lipid Res., July 1, 2000; 41(7): 1060 - 1066. [Abstract] [Full Text]
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C. Hop, A. Guilliatt, M. Daly, H. P. de Leeuw, H.-J. M. Brinkman, I. R. Peake, J. A. van Mourik, and H. Pannekoek Assembly of Multimeric von Willebrand Factor Directs Sorting of P-Selectin Arterioscler Thromb Vasc Biol, July 1, 2000; 20(7): 1763 - 1768. [Abstract] [Full Text] [PDF]
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Z. M. Dong, A. A. Brown, and D. D. Wagner Prominent Role of P-Selectin in the Development of Advanced Atherosclerosis in ApoE-Deficient Mice Circulation, May 16, 2000; 101(19): 2290 - 2295. [Abstract] [Full Text] [PDF]
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Y. Zou, Y. Hu, M. Mayr, H. Dietrich, G. Wick, and Q. Xu Reduced Neointima Hyperplasia of Vein Bypass Grafts in Intercellular Adhesion Molecule-1-Deficient Mice Circ. Res., March 3, 2000; 86(4): 434 - 440. [Abstract] [Full Text] [PDF]
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H. Dietrich, Y. Hu, Y. Zou, S. Dirnhofer, R. Kleindienst, G. Wick, and Q. Xu Mouse Model of Transplant Arteriosclerosis : Role of Intercellular Adhesion Molecule-1 Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 343 - 352. [Abstract] [Full Text] [PDF]
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R. G. Collins, R. Velji, N. V. Guevara, M. J. Hicks, L. Chan, and A. L. Beaudet P-Selectin or Intercellular Adhesion Molecule (Icam)-1 Deficiency Substantially Protects against Atherosclerosis in Apolipoprotein E-Deficient Mice J. Exp. Med., January 3, 2000; 191(1): 189 - 194. [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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G. Walker, A. C. Langheinrich, E. Dennhauser, R. M. Bohle, T. Dreyer, J. Kreuzer, H. Tillmanns, R. C. Braun-Dullaeus, and W. Haberbosch 3-Deazaadenosine Prevents Adhesion Molecule Expression and Atherosclerotic Lesion Formation in the Aortas of C57BL/6J Mice Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2673 - 2679. [Abstract] [Full Text] [PDF]
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D. C. Bullard, J. M. Mobley, J. M. Justen, L. M. Sly, J. G. Chosay, C. J. Dunn, J. R. Lindsey, A. L. Beaudet, and N. D. Staite Acceleration and Increased Severity of Collagen-Induced Arthritis in P-Selectin Mutant Mice J. Immunol., September 1, 1999; 163(5): 2844 - 2849. [Abstract] [Full Text] [PDF]
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 K. Fassbender, T. Bertsch, O. Mielke, F. Muhlhauser, and M. Hennerici Adhesion Molecules in Cerebrovascular Diseases : Evidence for an Inflammatory Endothelial Activation in Cerebral Large- and Small-Vessel Disease Stroke, August 1, 1999; 30(8): 1647 - 1650. [Abstract] [Full Text] [PDF]
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C. L. Ramos, Y. Huo, U. Jung, S. Ghosh, D. R. Manka, I. J. Sarembock, and K. Ley Direct Demonstration of P-Selectin– and VCAM-1–Dependent Mononuclear Cell Rolling in Early Atherosclerotic Lesions of Apolipoprotein E–Deficient Mice Circ. Res., June 11, 1999; 84(11): 1237 - 1244. [Abstract] [Full Text] [PDF]
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D. J. Lefer and D. N. Granger Monocyte Rolling in Early Atherogenesis : Vital Role in Lesion Development Circ. Res., June 11, 1999; 84(11): 1353 - 1355. [Full Text] [PDF]
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P. T. Shih, M.-L. Brennan, D. K. Vora, M. C. Territo, D. Strahl, M. J. Elices, A. J. Lusis, and J. A. Berliner Blocking Very Late Antigen-4 Integrin Decreases Leukocyte Entry and Fatty Streak Formation in Mice Fed an Atherogenic Diet Circ. Res., February 19, 1999; 84(3): 345 - 351. [Abstract] [Full Text] [PDF]
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G. A. Truskey, R. A. Herrmann, J. Kait, and K. M. Barber Focal Increases in Vascular Cell Adhesion Molecule-1 and Intimal Macrophages at Atherosclerosis-Susceptible Sites in the Rabbit Aorta After Short-Term Cholesterol Feeding Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 393 - 401. [Abstract] [Full Text] [PDF]
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L. E. Rohde, R. T. Lee, J. Rivero, M. Jamacochian, L. H. Arroyo, W. Briggs, N. Rifai, P. Libby, M. A. Creager, and P. M. Ridker Circulating Cell Adhesion Molecules Are Correlated With Ultrasound-Based Assessment of Carotid Atherosclerosis Arterioscler Thromb Vasc Biol, November 1, 1998; 18(11): 1765 - 1770. [Abstract] [Full Text] [PDF]
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 A. J. Palazzo, S. P. Jones, D. C. Anderson, D. N. Granger, and D. J. Lefer Coronary endothelial P-selectin in pathogenesis of myocardial ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, November 1, 1998; 275(5): H1865 - H1872. [Abstract] [Full Text] [PDF]
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Y. V. Bobryshev, R. S.A. Lord, T. Watanabe, and T. Ikezawa The cell adhesion molecule E-cadherin is widely expressed in human atherosclerotic lesions Cardiovasc Res, October 1, 1998; 40(1): 191 - 205. [Abstract] [Full Text] [PDF]
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 E. Trogan, R. P. Choudhury, H. M. Dansky, J. X. Rong, J. L. Breslow, and E. A. Fisher Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice PNAS, February 19, 2002; 99(4): 2234 - 2239. [Abstract] [Full Text] [PDF]
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