© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
ICAM-1 Deficiency Reduces Atherosclerotic Lesions in Double-Knockout Mice (ApoE-/-/ICAM-1-/-) Fed a Fat or a Chow Diet
From INSERM U331/Faculté de Médecine RTH Laënnec, Lyon, France (M.-C.B., C.C., E.C., G.B., J.L.M.); and the Department of Experimental Pathology, UMDS, Guy’s Hospital, London, UK (R.N.P.).
Correspondence to Marie-Claude Bourdillon, MD, INSERM, Unit 331/Site Cardiologique, 22 Avenue Doyen Lépine, Case Postale 18, F-69675 BRON Cedex France. E-mail bourdillon{at}lyon151.inserm.fr
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Abstract |
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Abstract—Intercellular adhesion molecule (ICAM)-1, a major adhesion molecule, plays a critical role in the homing of leukocytes to sites of atherosclerotic lesions. However, very little is known on the role of ICAM-1 in initiating and perpetuating vascular lesions in ApoE-/- mice fed a chow or a fat diet. This study has investigated the mean aortic lesions in mice (C57BL6 background) with a single-knockout (ApoE-/-) or double-knockout (DKO; ApoE-/-, ICAM-1-/-) fed a chow or a fat diet over a period of 3, 6, 15, and 20 weeks. A 3-fold reduction in lesion size was observed at all time points in DKO mice fed a chow diet. However, in DKO mice fed a fat diet, a marked reduction in the aortic lesion was observed at 3 and 15 weeks, which did not reach a significant level at 6 and 20 weeks. This study shows in essence that DKO mice are protected from developing significant lesions for up to 6 weeks when fed a chow diet and from 3 to 6 weeks when fed a fat diet. After 6 weeks, the lesion size of the DKO mice follows that of the single-knockout mice when fed a chow diet and gets to the same level in mice fed a fat diet. Plasma cholesterol levels were not altered as a result of ICAM-1 deficiency. These studies show that ICAM-1 is implicated in the formation and progression of atherosclerotic lesions.
Key Words: atherosclerosis • ICAM-1 • apolipoprotein E–deficient mice • aortic lesions
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Introduction |
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Atherosclerosis may be the result of genetic susceptibility combined with environmental factors such as diet, lifestyle, or possibly microbial infections.1 2 Oxidized LDL, one of the factors thought to affect vessel wall integrity,3 can lead to an inflammatory response.4 Such a response will induce endothelial cell activation, extravasation of leukocytes, and migratory/reparative process by vascular smooth muscle.5 6 Activated endothelium will express in sequence a series of adhesion molecules and powerful cofactors such as chemokines, which together will tether and activate leukocyte integrin complexes.7 Monocytes or T-lymphocytes, in the above-described process, will be allowed to extravasate to sites of inflammation.8 These adhesion molecules include intercellular adhesion molecule-1 (ICAM-1 or CD54),9 platelet-endothelial cell adhesion molecule-1 (PECAM-1 or CD 31),10 vascular cell adhesion molecule-1 (VCAM-1 or CD106),11 12 and P-selectin (CD 62P).13 ICAM-1, an adhesion molecule constitutively expressed by endothelial cells, has been shown to be upregulated in human atherosclerotic lesions.9
Atherosclerotic mice models (apolipoprotein E–deficient, ApoE-/-, and LDL receptor–deficient, LDLr-/-) have been shown to mimic human lesions closely.14 15 16 Moreover, lesions in these animals can be accentuated by the use of a hypercholesterolemic diet.17 18 However, it was observed by Roselaar et al,19 in a comparative study between ApoE and LDLr deficient mice, that the total area of atherosclerotic lesions was greater at all times in ApoE-/- than LDLr-/-. It is conceivable that the expression and role of adhesion molecules and cofactors may slightly differ between ApoE-/- and LDLr-/- mice. Very little is known at this stage on the role of ICAM-1 in initiating and perpetuating vascular lesions in ApoE-/- mice fed a fat or chow diet. However, qualitative and quantitative increases in endothelial ICAM-1 expression in ApoE-deficient mice are observed.20 21 Moreover, an anti–ICAM-1 monoclonal antibody in ApoE-/- mice greatly reduced the homing of monocytes to sites of atherosclerotic lesions.22 Finally, ICAM-1 knockout in a C57BL6 fat-fed model greatly reduced the size of vascular lesions.23 This study has investigated the size of aortic arch lesions in mice deficient in ApoE-/-, ICAM-1-/- (double-knockout, DKO) and compared them with ApoE-/--deficient (single-knockout, SKO) mice.
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Methods |
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Animal Handling
Surgical procedures and animal care strictly followed the Guidelines of the National Institutes of Health and Medical Research (decree No. 87-848 of October 19, 1987). All animals used in this study were ether-anesthetized before organ sampling.
Mice
The generation of the double target mutation mice model was
carried out with 2 original knockout lines: the
Icam1tm1Bay24 25 26 and the
ApoEtm1Unc.1 15 27 Dr N. Maeda
(University of North Carolina, Chapel Hill) and Dr A.L. Beaudet (Baylor
College of Medicine, Houston, Tex) kindly made the ApoE and
ICAM-1–deficient mice available to the European Network on
Atherosclerosis. Briefly,
ApoEtm1Unc chimeras were mated to C57BL/6J to
obtain B6129F1 animals homozygous for the disrupted gene. These
founders were back-crossed 6 times to C57BL/6J mice. A redirection by
embryo transfer and 3 additional back-cross generations on C57BL/6JIco
were conducted before intercrossing to obtain
C57BL/6JIco-ApoEtm1Unc breeding. The
C57BL/6JIco-Icam1tm1Bay breeding colony was also
established after embryo rederivation and back-cross with the C57BL/6J
mice colony. Both lines were maintained in specific and opportunistic
pathogen-free (SOPF) status by transfer of the SOPF mice and housing in
a filter-top cage system coupled with a laminar flow working station in
a full barrier unit. The double-mutant colony was generated under the
same housing conditions. Homozygous
C57BL/6JIco-ApoEtm1Unc and
C57BL/6JIco-Icam1tm1Bay were mated to obtain
heterozygous mutants. These double heterozygotes were intercrossed to
produce homozygous animals. These animals were identified by a double
protocol: total cholesterol level assay for ApoE mutants
and a polymerase chain reaction genotyping specific for ICAM-1. This
is, to our knowledge, the first reported production of a double
ApoE and ICAM-1 gene–deleted
mouse.28 Male mice were used throughout the entire
study. The weight of
ApoE-/- animals at 3, 5,
and 15 weeks was 9, 20, and 28 g, respectively; weight of
ApoE-/- and
ICAM-1-/- animals at 5,
15, and 20 weeks was 21, 30, and 31 g, respectively.
Identification of Knockout Animals
Total cholesterol measurement for ApoE-deficient
animals was performed on a blood sample collected from the
retro-orbital sinus of anesthetized animals. Commercially
available assay kits (Boehringer Mannheim) were used
(cholesterol is expressed in mmol/L). For
identification of ICAM-1 mutants, polymerase chain reaction
was done on tail fragments of animals. Genotyping and phenotyping of
animals were performed as previously indicated.26 The
sequences of the oligonucleotides (Genosys), with 3
sets of primers, were as follows: -ICAM-1 #2: 5'-ggA CAg gTC ggT CTT
gAC AA-3'; -ICAM-1 #2': 3'-CCT gTC CAg CCA gAA CTg TT-5'; -ICAM-1 #4:
5'-CAg CAC gTg CAg TTC CAg g-3'; -ICAM-1#4': 3'-gTC gTg CAC gTC AAg gTC
C-5'; -ICAM-1 #5: 5'-gTT CTT CTg AgC ggC gTC-3'; -ICAM-1 #5': 3'-CAA
gAA gAC TCg CCg CAg-5'.
Experimental Design
Both ApoE-deficient mice (n=45) and double ApoE and ICAM-1
homozygous mutants (n=45) were weaned at 3 weeks of age and maintained
on chow ("Souriffarat" breeding diet, standard formulation,
pellets, irradiated at 25 kGy) for 1 week (control group at time 0).
Single ApoE-/- and double
ApoE-/-,
ICAM-1-/- mutant animals
were analyzed after 3, 6, 15, and 20 weeks of either chow or
fat diet feeding (n=5 mice per group). The fat diet consisted in a
Western type (21% fat, 0.15% cholesterol, special high
fat formulation, and powder, irradiated at 25 kGy). The
cholesterol levels of 5 animals were analyzed per
time point and per diet.
Histological and Morphometric Analysis
Animals were killed after having been anesthetized by
ether inhalation. The heart, after incision of the thorax, was briefly
perfused with 4% paraformaldehyde in PBS solution. The
heart and the contiguous thoracic aorta were then cut off and rapidly
embedded in tissue-Tek OCT compound (Miles). OCT-treated samples were
then frozen in liquid nitrogen. Sections (8 µm thick) were
mounted on gelatin-coated slides and stored at -80°C. Before
staining, sections were air-dried and fixed in cold acetone. Lipid
staining was performed by oil red O (ORO). In addition, standard
hematoxylin-phloxine-safranin staining was also performed.
Immunohistochemistry
Macrophages were stained with MOMA-2 (rat antibody
directed against murine monocytes/macrophages, Serotec)
monoclonal antibody. A nonimmune monoclonal antibody of the same
species and class as the MOMA-2 antibody, a rat IgG2a (Pharmingen), was
used as a negative control. A biotinylated rabbit anti-rat/mouse
adsorbed IgG was used as second antibody (Vector Laboratory). Sections
were developed with avidin-biotin-horseradish peroxidase complex before
AEC (3-amino-9-ethylcarbazole) staining procedures as
described.29
Quantimetry
The ratio of lesion area to media area was performed through the
use of a Quantimet 600 Leica analyzer. Morphometric
analyses of intima lesion area over media area were carried out
on the whole circumference of the proximal aortic arch, with the use of
a previously described quantification method.14 23 30 The
number of sections used per animal was at least 5 per animal and per
time point. Measurements were performed on ORO-stained slides for the
different weeks of feeding (5 mice per group). Results are expressed as
mean±SEM of intima/media area ratio. The differences between SKO and
DKO mice groups were computed by unpaired Student’s t
test.
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Results |
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Cholesterol Levels
Animals from the two groups, fed on a chow diet for various lengths of time (0, 3, 6, 15, and 20 weeks), showed no differences in cholesterol levels (Figure 1
). In addition, no differences in
cholesterol levels for animals fed a fat diet were observed
at 3, 6, and 15 weeks. It should be noted that cholesterol
levels in chow-fed animals were in general lower than those observed
for fat-fed animals. We observed a drop in cholesterol
levels in 15-week-old animals fed a fat diet. It is conceivable that in
these animals, at such a time point and cholesterol level,
there is more active cholesterol transfer/sequestration in
tissues and hence a lower circulating level. In one instance,
cholesterol levels differed between animal types in that
SKO animals at 20 weeks, on a fat diet only, showed a significantly
higher cholesterol level than in the DKO (Figure 1).
At this time point, the SKO somehow differ from the DKO in their
capacity to transfer cholesterol from circulation to
tissues. However, in that case, no difference in lesion area was
observed. All other cholesterol results showed no
differences between animal types.
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Vascular Lesions
The aortic arch region in SKO and DKO was investigated in weaned
animals and after feeding a chow or a fat diet (3, 6, 15, and 20
weeks). Lesions increased in severity through all time points of the
experiment in both the SKO and DKO animals. They were qualitatively
similar in both groups and resembled those previously
described.14 However, those in the DKO mice were of less
severity than in the SKO (Figure 2, A-B,
E-F, G-H). Macrophages were immunostained in the
core and at the surface of lesions (Figure 2, C-F). Moreover,
macrophages were also observed beneath the
endothelial cell layer. When classic advanced
atherosclerotic lesions were produced in the aortic arch of animals fed
a chow diet for 20 weeks, ORO-stained foam cells were seen in the
shoulders and core of plaques (Figure 2, G-H). Smooth muscle
proliferation, calcifications, and cholesterol clefts were
also observed in extended lesions of mice fed a fat diet for 20 weeks
(Figure 2, I-J).
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Lesion Area/Media Area
The protective effect resulting from ICAM-1 deficiency is seen in
all DKO animals compared with SKO throughout the whole feeding period.
Indeed, at 3, 6, 15, and 20 weeks, chow-fed DKO mice showed a
lesion/media area ratio that was significantly lower compared with the
SKO (Figure 3A and
Table). This protective effect, in
the absence of ICAM-1 expression, was present at all times in
chow-fed animals. Percentage reduction in lesion area/media area for 3,
6, 15, and 20 weeks was 77%, 55%, 62%, and 54%, respectively.
Likewise, in fat-fed animals, the lack of ICAM-1 reduced lesion size to
some extent at all time points (Figure 3B and Table).
Percentage reduction in lesion/media area ratio for 3, 6, 15, and 20
weeks was 94%, 55%, 76%, and 17%, respectively. However, at 6 and
20 weeks only, the decreases were not significant (Table).
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Discussion |
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This study shows for the first time that ICAM-1 plays a crucial role in modulating the size of lesions in aortic arch isolated from ApoE-/- deficient mice fed either a chow or a fat diet. Indeed, results show a decreased ratio in intima to media area in all mice deficient in ApoE-/-, ICAM-1-/- compared with ApoE-/- animals, although in 2 groups of the 8, the difference did not achieve statistical significance. The lack of significance in these groups may be attributable to the inherent variability of the atherosclerotic process and the small groups of 5 animals. In contrast, plasma cholesterol did not appear to be implicated in affecting lesion size. As previously reported,13 focal atherosclerotic lesions seen in this study resemble human lesions. Moreover, in line with previously published data,14 17 31 the appearances of the atherosclerotic lesions are characterized by typical lipid deposition, cellular infiltration, and smooth muscle cell proliferation.
Atherosclerotic lesions may be the result of some form of inflammation
induced by the presence of oxidized LDL, Chlamydia
pneumoniae,32 or viral or other factors occurring at
the level of the vessel wall.33 Vascular
endothelial cells, activated at sites of
inflammation, interact with different leukocyte subtypes through
adhesion molecules and various cofactors and are thought to play a key
role in the initiation and perpetuation of atherosclerotic
lesions.34 Several studies have observed an initial
increase in intimal leukocyte accumulation35 that is
followed by a decreased density of leukocyte recruitment within
atherosclerotic walls.19 Among a number of adhesion
molecules implicated in the homing of leukocytes to sites of
inflammation, endothelial ICAM-1 and its leukocyte
ligand CD11a/CD18 (also known as
Lß2 or LFA-1) play a
major role in this process.36 37 Monocytes attracted by
endothelial released MCP-1 can bind directly through
CD11a/CD18 to vascular ICAM-1 and/or by fibrinogen through CD11b/CD18
(also known as Mß2 or
MAC-1) and ICAM-1.38
Constitutive levels of ICAM-1 in mice differ markedly from one organ to another. Endothelial ICAM-1 expression is highest in the heart vessels compared with the brain, mesentery, or small intestine.39 Recent qualitative and quantitative data report a significant increase in ICAM-1 expression in the ApoE-deficient mouse.20 21 Moreover, and very significantly, observations made on human coronaries and carotids show ICAM-1 expression correlated to vascular lesions.9 ICAM-1 as well as VCAM-1 are expressed in a flow-dependent manner.40 Upregulation of ICAM-1 in cultured human and rabbit arterial endothelial cells has been shown to occur after lysophosphatidylcholine treatment.41 Moreover, lysophosphatidylcholine induced the expression of ICAM-1 on endothelium derived from human iliac arteries but not from umbilical veins.41 It is of interest to note that high levels of lysophosphatidylcholine are present in hyperlipidemia. Deficiency of ICAM-1 expression in C57BL6 fat-fed animals showed a 75% protection against atherosclerosis when compared with wild-type animals.23 However, one should note that ApoE-deficient animals fed a fat diet probably show lesions that are closer, compared with C57BL6, to those seen in human. Our data support a role for ICAM-1 at all stages of atherosclerosis in chow-fed animals. However, this does not appear to be the case for fat-fed animals. Indeed, ICAM-1 appears to have the greatest impact at the early stages of atherosclerosis in animals fed a fat diet. Interestingly, monoclonal antibodies directed to ICAM-1 in ApoE-deficient animals on a chow diet reduced the homing of macrophages to atherosclerotic plaques by 65%.22 In addition, the use of anti–ICAM-1 monoclonal antibodies in hypercholesterolemic rats significantly reduced the homing of macrophages to the intima by 42%.42 It is most probable that an absence of ICAM-1 greatly reduces the inflow of monocytes to sites of lesions and hence affects the ratio in intima to media area of aortic arch.
The work presented in this study and that from other teams clearly indicate that ICAM-1 is a key target implicated in cell-cell interactions leading to the initiation and perpetuation of atherosclerotic lesions. However, great care must be taken in blocking vascular ICAM-1 expression because it impairs inflammatory and immune responses in C57BL6 mice.24 It should be noted that ICAM-1 expression is only part of the mechanism implicated in the homing of leukocytes to sites of vascular lesions; other adhesion molecules, for instance, P-selectin, have been implicated in gene-deleted mice.43 Furthermore, knocking out MCP-1 or its receptor in LDL-/- or ApoE-/- mice, respectively, will also significantly decrease lesion formation.44 45 In conclusion, adhesion and transmigration mediated by several interacting molecular mechanisms appear to be essential for monocyte traffic in atherosclerosis, and this study provides further evidence of the importance of these phenomena in the pathogenesis of the disease.
While this manuscript was being revised, the work by Collins et al46 has been published. The authors report atherosclerosis in ApoE knockout animals also having a deficiency in ICAM-1 or P-selectin or E-selectin. A part of this study focused on the effect of ICAM-1 deficiency on animals at 20 weeks of diet on a chow diet. A significant reduction in lesion area was also observed in both male and female mice.
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Acknowledgments |
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This work was supported by the French Ministry of Education Scientific Research (grant MESR ACC-SV9) and by the European Network on Atherosclerosis (BIOMED 2, grant PL 1195). We would like to thank George Canard, Dr Patrick Hardy (from Transgenic Alliance-Iffa Credo, L’Arbresle), Dr Catherine Souchier, Dr Jean-Claude Bernengo (Centre Commun de Quantimétrie, Université Claude-Bernard, Lyon), and Odile Gayet for their excellent help and advice during the course of this work.
Received March 21, 2000; accepted July 10, 2000.
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