Brief Review |
From the Department of Pathology and Laboratory Medicine and the Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill.
Correspondence to Dr Nobuyo Maeda, Department of Pathology and Laboratory Medicine, CB No. 7525, University of North Carolina, Chapel Hill, NC 27599-7525. E-mail nobuyo{at}med.unc.edu
| Abstract |
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Key Words: apoE LDL receptor hypertension inflammation diabetes
| The Mouse as a Model System for Studying Atherosclerosis |
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ApoE is an amphipathic protein that plays a pivotal role in lipoprotein trafficking. ApoE is a constituent of chylomicrons, VLDL, and HDL and acts as a ligand for the receptor-mediated clearance of these particles.14 Mice lacking apoE have plasma cholesterol levels that are 4 to 5 times normal and develop atherosclerotic lesions spontaneously, even when fed a normal chow diet, which is low in fat and cholesterol. The lesions resemble human lesions and progress over time from an initial fatty streak to a complex lesion with a fibrous cap,15 16 and lesion development can be accelerated by a high-fat, high-cholesterol diet.17 Mice lacking the LDLR have less overt disease, with a modest 2 times normal plasma cholesterol level when maintained on a normal chow diet, and they develop atherosclerosis only slowly.18 However, in response to a high-fat, high-cholesterol diet, LDLR-deficient mice exhibit massive elevations in plasma cholesterol and rapidly develop atherosclerotic lesions throughout the aorta.19 There is much less published data on the kinetics of lesion development in LDLR-deficient mice than in apoE-deficient mice. Nevertheless, the lesions that develop in Apoe- and Ldlr-deficient mice are generally the same, with the plaques developing in a time-dependent manner, starting from the proximal aorta and spreading toward the distal aorta, and particularly involving locations where blood flow is disturbed. Although the merits of each model and of different methods of assessing the extent of atherosclerosis are still debated, results with the 2 models are generally comparable and largely independent of whether the quantification is based on the lipid content of the aorta, the surface area of lesions in the aortic tree, cross-sectional plaque size in the proximal aorta, or cellular composition of plaque materials. The predictable development of plaques in these mutants, along with other more general advantages of mice, such as their small size, short generation time, and relative ease of care, have quickly made the mouse a very effective and practical model for the study of atherosclerosis. However, the most important advantage is the availability of genetically defined inbred and mutant strains and the well-established means of using these strains to manipulate the mouse genome.
In humans, current evidence suggests that susceptibility to atherosclerosis is most likely due to unfavorable combinations of mutations affecting genes in several pathways, but our knowledge about which genes are involved is limited.20 Genetic analysis in mice provides a powerful approach toward identifying the genes and pathways involved. For example, crosses between inbred strains of mice have led to the identification of several atherosclerotic quantitative trait loci (QTL) controlling strain-specific differences in diet-induced atherosclerosis susceptibility.3 21 Likewise, valuable information about atherosclerotic modifiers has been obtained by studying crosses of Apoe-/- or Ldlr-/- mice with mice carrying other mutations.
The use of Apoe-/- and Ldlr-/- mice to develop an understanding of the genetic factors that modify atherogenesis provides the theme for this review. Other atherogenic mouse models and the effects of modifying genes related to lipid metabolism are well studied and have recently been reviewed.11 12 13 22 Consequently, in the present review, we consider how atherosclerosis is modified by 4 other variables: inflammation, disturbances in glucose metabolism, hypertension (HTN), and coagulation/fibrinolysis. These conditions are a source of continuous injurious stimuli that can trigger the early stages of atherosclerosis. We include several examples showing how the mouse has been used to test human polymorphisms as potential atherosclerotic modifiers based on prior epidemiological studies. Finally, we discuss some of the current limitations of mouse models of atherosclerosis and suggest where future improvements might be made.
| Atherosclerosis and Inflammation |
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In 1993, Ross20 suggested in his landmark review that
atherosclerosis can largely be viewed as a
self-perpetuating inflammatory disease. Accordingly, we begin by
considering the genes listed in Table 1
that are known to affect inflammation and that have been tested for
involvement in atherogenesis by using
Apoe-/- and/or
Ldlr-/- mice. As Ross elaborated in
his review, the atherosclerotic inflammatory response progresses in
discrete stages, which are so characteristic that the presence of
certain inflammatory cell types can be used to define the progression
of atherosclerotic lesions.
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In the early stages, the lesions are fatty streaks composed of
lipid-rich macrophages. At this stage, molecules involved in
leukocyte (and particularly, monocyte/macrophage) function,
recruitment, rolling, adherence, transendothelial
migration, and activation are likely to play key roles. The importance
of monocytes/macrophages in the pathogenesis of
atherosclerosis has been confirmed by experiments
affecting molecules in these pathways. For example, osteopetrotic
(op) mice have a mutation in the gene for macrophage
colony stimulating factor (MCSF) that causes a severe decrease in the
number of monocytes/macrophages in the mutant animals.
ApoE-deficient mice crossed with op mice produce offspring
that develop much smaller lesions than do control apoE-deficient
mice.23 In fact, the absence of MCSF causes the
single, largest decrease in lesion size of all of the genes that have
been tested to date (Table 1
, line 14). Importantly, there is a
gene-dosage effect, as MCSF heterozygotes also have reduced lesions.
Likewise, administration of an antibody against the receptor for MCSF
reduces lesion size in apoE-deficient mice.24 Cell
adhesion molecules that facilitate monocyte rolling and adherence also
influence atherogenesis (see lines 10 to 13 of Table 1
),25 26 27 28 as do cytokines that affect
monocyte recruitment and activation (reviewed in Reference
29 ). Monocyte chemoattractant protein-1 (MCP-1) is a
cytokine that acts through its receptor, CC chemokine receptor
2 (CCR2), on monocytes, macrophages, and T lymphocytes. The
absence of MCP-1 dramatically decreases lesion size in LDLR-deficient
mice30 (see line 1, Table 1
). Similarly, the
absence or decrease of CCR2 causes a reduction in lesion size in
apoE-deficient mice31 32 (see lines 2 and 3, Table 1
). In the opposite direction, irradiated
Apoe-/- mice, in which the bone
marrow has been replaced with cells that overexpress MCP-1, have an
increased atherosclerotic lesion size33 (see line 4,
Table 1
).
Although these alterations in the MCSF and MCP-1 pathways have marked effects on the progression of atherosclerosis, they do not completely eliminate macrophage-derived foam cell development and fatty streak formation. Furthermore, the plaques in these mice still progress with time to more complex lesions. Additionally, although most of the evidence implicates macrophages as proatherosclerotic mediators, there is some evidence that they have some atheroprotective effects.34
The fatty streak progresses to intermediate lesions that contain
monoclonal expansions of smooth muscle cells as well as increased
numbers of macrophages and T cells. The potential role of T and
B lymphocytes has been extensively evaluated, revealing a complex
picture. Mice deficient in either recombinase-activating gene 1 or 2
(RAG1 or RAG2) do not produce functional T or B cells owing to a defect
in V(D)J recombination. Experiments with
Apoe-/- mice on a high-fat diet
showed that the total absence of T and B cells caused by the absence of
RAG1 or RAG2 did not affect lesion development.35 36
However, on a normal chow diet,
Apoe-/- mice deficient in RAG1 have
a modest decrease in lesion size compared with
Apoe-/- controls (see Table 1
, lines 15 and 16).35 The role of T cells in
atherogenesis has been investigated by studying genetic alterations of
the CD40-CD154 interaction37 or by the administration of
antibodies against CD154.38 CD40, a cell surface receptor
found on many immune cells, shares homology with tumor necrosis factor
receptors. CD154, the ligand for CD40, is thought to be restricted to
CD4+ T lymphocytes. When Ldlr-/-
mice are fed a high-fat diet, treatment with antibodies to CD154
reduces expression of adhesion molecules and lesion
size.37 Consistent with this observation,
Apoe-/- mice that are also deficient
in CD154 have a dramatic 5-fold decrease in lesion size, and the
plaques in these mice also have a more stable, collagen-rich plaque
phenotype with a reduced T cell/macrophage content (see
line 5, Table 1
). Similar plaque phenotypes have been
seen in mice lacking the interferon-
receptor
(IFN-
R)39 (line 6, Table 1
).
The small-molecule mediators of acute inflammation, such as histamine, prostaglandins, leukotrienes, and throm-boxanes, have not been extensively studied as atherosclerotic modifiers despite the observation that some anti-inflammatory agents such as aspirin clearly reduce the risk of atherosclerotically mediated cardiac events.40 41 Two experiments are, however, relevant: disruption of the 12/15-lipoxygenase gene in Apoe-/- mice decreases atherosclerotic lesions,42 and transgenically overexpressing group IIa phospholipase A2 (sPLA2) in C57BL/6 mice fed a high-fat diet increases lesion size.43 Thus, arachidonic acid metabolites have demonstrable effects on lesion development.
Although macrophages and T cells are important in
atherogenesis, neutrophils appear to be less important. Neutrophils are
not notable in atherosclerotic lesions, even in CCR2-deficient,
Apoe-/- mice, which have persistent
neutrophilia in other tissues after inflammatory
stimulation.44 The C-X-C chemokine receptor 2 (CXCR2)
is the receptor for interleukin-8 and growth-regulated oncogene
(GRO
) and is predominantly, though not exclusively, expressed in
neutrophils. Irradiated Ldlr-/-
mice, whose bone marrow is replaced with cells lacking the mouse
homolog to CXCR2, develop smaller lesions45 (see line
7, Table 1
), indicating that this pathway is important in
atherogenesis. However, as the authors suggest, the CXCR2 pathway may
be enhancing atherogenesis by promoting monocyte adhesion, recruitment,
and activation rather than through neutrophil
actions.29 45
| Hyperglycemia and Atherosclerosis |
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In humans and mice, diabetes is clearly a polygenic disorder,57 58 59 and although some chromosomal regions have been linked to diabetes, identification of the genes involved has proven difficult. New diabetic mouse models promise to change this situation. The insulin receptor (IR) is a receptor tyrosine kinase, and binding of insulin to the IR stimulates phosphorylation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), which then activate other signaling molecules in the insulin signaling cascade. Mice homozygously deficient in either IR or IRS-2 die prematurely,60 61 whereas mice deficient in IRS-1 have severe growth retardation.62 63 In contrast, compound heterozygotes, which are heterozygous for a normal copy and a disrupted copy of IR, IRS-1, and/or IRS-2, survive and develop insulin-resistant diabetes.64 65 The insulin-responsive glucose transporter, GLUT4, is important in postprandial glucose metabolism as a facilitative transporter in skeletal muscle and adipose tissue. Mice heterozygous for disruption of GLUT4 develop hyperinsulinemia and hyperglycemia as they age.66 The phenotypes in these mice are complex, because both the IRS-1deficient and GLUT4 heterozygous animals also have markedly elevated blood pressure.66 67 Nevertheless, exciting and informative results relating diabetes and atherosclerosis are likely to follow when these new diabetic models are combined with apoE or LDLR deficiencies.
| Interaction Between HTN and Atherosclerosis |
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Many of the animal model studies of HTN plus
atherosclerosis have been made by using surgical
treatments to induce chronic coarctation of the abdominal aorta. Aortic
constriction increases both the pressure and the lesions proximal to
the constriction in hypercholesterolemic
rabbits.73 74 Surgical constriction of the renal artery
also increases atherosclerosis in
rabbits.75 To date, these surgical approaches have not
been applied to study HTN and atherogenesis in the mouse. Another
approach has utilized drugs to raise or lower blood
pressure.76 For instance, infusion of agents that increase
blood pressure, like angiotensin II or
NG-nitro-L-arginine
methyl ester, increases atherosclerosis in some
models,77 78 79 whereas treatment of HTN with various
antihypertensive drugs decreases atherosclerosis in
several animal models (reviewed in Reference 76 ).
Antihypertensive drug treatment studies in atherogenic mouse models
have yielded conflicting data. Some studies have shown atheroprotective
effects of antihypertension therapy without demonstrably lowering the
blood pressure.80 81 82 However, in 1 of the most
interesting studies, Makaritsis et al83 showed that
neither
-adrenergic nor angiotensin receptor blockade
alone lowered blood pressure or decreased lesions in
Apoe-/- mice, but
simultaneous blockade decreased both blood
pressure and lesion size. Furthermore, we observed that chronic
treatment with the angiotensin-converting enzyme (ACE)
inhibitor enalapril did not significantly reduce
atherosclerosis or lower the blood pressure of
apoE-deficient mice, which are inherently
normotensive.84
Currently, there are only a few genetic models with combined
atherosclerosis and HTN. In one study, mice that
express both a human renin transgene and a human
angiotensinogen transgene were generated on a C57BL/6
genetic background. When fed a high-cholesterol diet, these
mice have an elevated blood pressure (by 20 mm Hg) and develop
larger lesions than equivalent nontransgenic mice.85
Recently, we have developed a genetic model in which HTN is combined
with atherosclerosis by crossing apoE-deficient mice
with endothelial nitric oxide synthase
(eNOS-/-)deficient
mice.84 Similar results were obtained in
eNOS-/-,
Apoe-/- mice maintained on a high-fat
diet.86 eNOS serves important basal regulatory
functions in the vasculature. In response to stimuli such as shear
stress or acetylcholine, eNOS catalyzes the production of NO,
which diffuses across the endothelial cell membrane
into smooth muscle cells, inducing vasodilation. It also acts locally
to prevent platelet and leukocyte adhesion.87 In
comparison with the Apoe-/-
controls, doubly deficient
eNOS-/-,
Apoe-/- mice are hypertensive (by 20
mm Hg), have atherosclerotic lesions twice the size, and also develop
kidney damage (see Table 3
, lines 1 and
2). These deleterious effects of eNOS deficiency were reduced by
chronic treatment with enalapril at the same dose that was ineffective
in Apoe-/- mice that were
eNOS+/+ and had a normal blood
pressure.84 These experiments are also notable
because they demonstrate that in mice, the atheroprotective effects of
enalapril are independent of NO production through eNOS and
that a measurable component of increased
atherosclerosis is due to an increase in blood
pressure.
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The distribution of atherosclerotic plaques appears to be different in eNOS-/- Apoe-/- mice than in Apoe-/- mice, potentially shedding light on one mechanism that may determine the localization of atheromas. Plaques develop in the descending and abdominal aortas of the double-knockout mice even by 4 months of age. In contrast, in apoE-deficient mice, lesions do not become prominent in these regions until 8 months of age. As previously mentioned, atherosclerotic plaques tend to develop in areas where blood flow is turbulent and where flow-induced shear stress is low but where pressure-induced vascular wall strain is high.69 88 89 It is possible that normal eNOS function prevents the development of plaques in areas of high shear stress, so that an absence of eNOS leads to plaque development in these areas. Cross-breeding Apoe-/- or Ldlr-/- mice with other genetic models of HTN is desirable, because analysis with various antihypertensive treatments may clarify the causative link between increased blood pressure and enhanced atherosclerosis and perhaps identify better treatment strategies.
A powerful approach to confirm genes that modify the severity of atherosclerosis is to design experiments in mice to test whether gene polymorphisms identified in human epidemiological association studies actually affect atherosclerosis. There are many challenges in studying complex diseases such as atherosclerosis in humans. Not only are the environmental and genetic backgrounds of individuals diverse, but also there is a high likelihood that differences will occur in other unsuspected genes tightly linked to a candidate gene. Effects due to linked differences can therefore easily be misinterpreted as due to differences in the candidate gene. Well-designed experiments in mice can eliminate these complications, although only a few such tests have yet been done.
The human ACE gene provides an example. This gene has 2
common alleles, I and D, which differ by the
presence (I) or absence (D) of an Alu sequence in
intron 16. Individuals homozygous for the I allele have
an
35% lower ACE activity than do individuals homozygous for the
D allele.90 Several large studies have
examined the frequencies of these ACE gene variants in
case-control subjects for atherosclerosis or MI.
Association of the ACE genotype with disease was
found in some studies but not in others.91 92 93 We
have therefore examined the effect of plasma ACE levels on diet-induced
atherosclerosis by using Apoe-heterozygous
mice combined with 1 (±) or 2 (+/+) copies of the Ace gene.
The 2-copy animals have normal plasma ACE levels, whereas the 1-copy
animals have half-normal levels (the genetic equivalent of 50%
inhibition by a converting-enzyme inhibitor). The mice were
all from an F1 generation between C57BL/6 and 129
mice, so that their genetic backgrounds were completely identical
except for their Ace gene status. The results showed that
plasma ACE activity differences similar to those seen in humans did not
lead to differences in blood pressure or in atherosclerotic lesion
size. These results suggest that variation in the ACE gene
in humans is unlikely to affect the development of
atherosclerosis or HTN in humans (see Table 3
,
line 3).94 95
| Coagulation, Fibrinolysis, and Atherosclerosis |
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Plasminogen activator inhibitor-1
(PAI-1) is another member of the fibrin/fibrinolytic pathway whose
association with coronary heart disease has been extensively
tested in humans, with mixed results.99 100 101 PAI-1 is the
primary inhibitor of the conversion of
plasminogen to plasmin. Plasminogen is a
proenzyme that is converted to its active form, plasmin, by
physiological activators such as tissue
plasminogen activator and urokinase
plasminogen activator. Plasmin-mediated
proteolysis is critical to the dissolution of fibrin matrixes in
arterial and venous thrombi. The balance between
plasminogen activation/inactivation may be critical in the
development of atherosclerosis. A common
polymorphism in the promoter region of the PAI-1 gene,
which causes varied expression of the gene, is consequently a candidate
for affecting atherosclerosis. Experiments by Sjoland
et al102 in both Apoe- and
Ldlr-deficient mice on a C57BL/6 background have shown that
neither the absence of PAI-1 nor its overexpression by a transgene
affects lesion development, suggesting that the levels of PAI-1 do not
affect the development of atherosclerosis (see Table 3
, lines 6 and 7). Nevertheless, the absence of
plasminogen greatly increases atherosclerotic lesion size
in Apoe-/- mice of a hybrid
C57BL/6/NIH Black Swiss/129 background103 (see Table 3
, line 5). To reconcile these experiments, the authors proposed
that alternative inhibitors of plasminogen
activators may exist in mice, so that the effects of
manipulating the PAI-1 locus are masked, or that the
increased infectious complications that are present in
plasminogen-null mice may affect the development of
atherosclerosis.102
| Other Considerations |
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In evaluating causative links between gene mutations and
atherosclerosis, the choice between
Apoe-/- or
Ldlr-/- mice is not of crucial
importance, as there is no compelling evidence that either of these
models is inherently better than the other. We have not found any
examples in the literature in which the same gene, either overexpressed
or knocked out in both Apoe-deficient and
Ldlr-deficient mice, gives different results (see Table 1
, lines 1 to 3 and 10 and Table 3
, lines 6 and 7).
However, it is important that analyses of these mouse models be
well controlled to ensure that the genetic backgrounds of the parental
strains, in most cases C57BL/6 as opposed to 129, does not bias the
results. Presently, this complication is avoided through repeated
back-crossing to the C57BL/6 genetic background. Less rigorous studies
use littermates to control for genetic variability, on the assumption
that genetic differences not linked to the locus of interest will be
randomly distributed among the offspring. However, if only a small
number of littermates are used, nonrandom segregation of any nonlinked
differences may bias the results. The effects of genes linked to the
mutation are more difficult to eliminate unless other strict breeding
strategies are employed (reviewed in References 11 and
105 ). Thus, special caution is necessary when multiple
genetic alterations (often available only on a 129 genetic background)
are combined and bred with an atherosclerotic model (often on a C57BL/6
genetic background). The situation is particularly difficult when the
combined mutations cause decreased lesions, because every altered locus
generated in 129 embryonic stem cells carries with it linked DNA
from the 129 strain, which is an
atherosclerosis-resistant strain when compared
with C57BL/6. A spurious decrease in lesion size is consequently more
likely than a spurious increase in lesion size.
Atherosclerotic modifiers differ between mouse strains. Thus, plaque development caused by the absence of apoE is different on an FBV or a C3H genetic background compared with the C57BL/6 background.106 107 Also, a naturally occurring apoE deficiency in Mus musculus molossinius, with severe xanthomas and a shortened life span, was recently identified, but these mice have relatively small aortic plaques when compared with Apoe-/- mice on a C57BL/6 background.108 Identification of the loci that contribute to strain differences in atherosclerotic susceptibility will likely yield new candidates for human susceptibility, and Apoe-/- or Ldlr-/- mutations should accelerate their identification. Nevertheless, testing each gene effect on multiple genetic backgrounds by breeding is of borderline practicality. Regenerating interesting mutations such as Apoe-/- or Ldlr-/- by using embryonic stem cells from inbred strains other than 129 (such as atherosclerosis-susceptible C57BL/6 mice or the less-susceptible strains DBA/1 or BALB/c) may prove easier than the time-consuming, costly, and labor-intensive task of back-crossing to congenicity.
Further uses of gene targeting and transgenic mice assure that additional models of atherosclerosis will be developed. The development of mouse models in which plaque rupture occurs is particularly important, as discussed above. Also, the application of Cre-lox technology to develop tissue-specific and/or time-dependent knockouts109 will prove valuable for dissecting the mechanism of atherosclerosis, although such animals do not strictly represent inherited genetic variations, which are of course lifelong and affect multiple organ systems.
Finally, we emphasize that mouse knockout experiments are the genetic equivalent of recessively inherited conditions in humans due to the loss of gene function. This type of condition makes only a small contribution to the total human burden of atherosclerosis. The pattern of inheritance of atherosclerosis in humans is more compatible with susceptibility being due to combinations of small, quantitative changes in gene function, analogous to the situation that occurs in mice that are heterozygous for a gene modification. Thus, it is extremely important not only to study whether a complete absence of gene function affects atherosclerosis but also to determine whether quantitative changes in the expression of genes affect the condition. Genes that affect atherosclerosis in mice in the heterozygous state are probably the best candidate genes for being related to atherosclerosis susceptibility in humans. Thus, the study of heterozygotes is extremely important (for more on the importance of quantitative changes, see Reference 95 ).
| Conclusions: "Mice to Humans" and "Humans to Mice" |
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Human polymorphisms shown to be associated with atherosclerosis should be tested for causation in mice. One way to carry out such tests is to "humanize" the mouse by generating animals that have the same allelic differences, such as single-nucleotide polymorphisms (SNPs), that occur in human populations. For example, the effects of a pair of SNP differences in the human APOE gene were evaluated in mice. The 3 common APOE alleles in the human population, APOE*2, APOE*3, and APOE*4, differ only in 2 coding nucleotides resulting in amino acid changes. Various population-based studies have suggested that these small differences influence lipid metabolism in humans.111 Recently, our laboratory used mice with a targeted replacement of the endogenous mouse allele with the different human alleles to show that protein structures coded by these alleles are responsible for plasma retention of lipoproteins and atherosclerosis susceptibility.112 113
The effect of any single SNP is likely to be small. However, eventually it will be possible to combine many of these small variations in a single mouse. Comparing various "combinations" should yield important information about which combinations are particularly deleterious and which are protective. It is certainly not easy to breed these "compound" mutants. However, once "prototype" animals have been obtained, cloning via nuclear transfer is a potential future way to facilitate the generation of sufficient numbers of these animals to carry out meaningful studies.114 115
The ability to go back and forth between humans and mice, made possible by targeted mouse models, has and will continue to play an integral part in the study of atherosclerosis. The pathogenesis of atherosclerosis is complex, polygenic, and multifactorial. Knowledge of the genetic determinants of atherosclerosis, aided by mouse studies, will allow us to identify disease-prone persons and design specific preventive measures for them and treatments tailored for those for whom prevention is no longer an option.
| Acknowledgments |
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Received June 13, 2000; accepted August 22, 2000.
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B. R. Kwak, F. Mulhaupt, N. Veillard, D. B. Gros, and F. Mach Altered Pattern of Vascular Connexin Expression in Atherosclerotic Plaques Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 225 - 230. [Abstract] [Full Text] [PDF] |
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W.-J. ZHANG and B. FREI {alpha}-Lipoic acid inhibits TNF-{alpha}-induced NF-{kappa}B activation and adhesion molecule expression in human aortic endothelial cells FASEB J, November 1, 2001; 15(13): 2423 - 2432. [Abstract] [Full Text] [PDF] |
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S. R. Lentz Does Homocysteine Promote Atherosclerosis? Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1385 - 1386. [Full Text] [PDF] |
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S.-K. Moon, L. J. Thompson, N. Madamanchi, S. Ballinger, J. Papaconstantinou, C. Horaist, M. S. Runge, and C. Patterson Aging, oxidative responses, and proliferative capacity in cultured mouse aortic smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2779 - H2788. [Abstract] [Full Text] [PDF] |
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Y. Chu, D. D. Heistad, K. L. Knudtson, K. G. Lamping, and F. M. Faraci Quantification of mRNA for Endothelial NO Synthase in Mouse Blood Vessels by Real-Time Polymerase Chain Reaction Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 611 - 616. [Abstract] [Full Text] [PDF] |
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