Articles |
From INSERM U397 (R.E., J.-F.A., J.-C.F., F.B.) and INSERM U466 (M.-T.P.), Institut L. Bugnard, Toulouse Cédex, France; RPR-Gencell, Atherosclerosis Department (N.D.), Vitry sur Seine Cédex, France; and INSERM U325 et Serlia (C.F.), Institut Pasteur, Lille Cédex, France.
Correspondence to Dr F. Bayard, INSERM U397, Institut L. Bugnard, 1 avenue Jean Poulhès, 31054 Toulouse Cédex, France. E-mail bayard{at}rangueil.inserm.fr
| Abstract |
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Key Words: fatty streak formation apolipoproteins
| Introduction |
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Apolipoprotein Edeficient (apoE KO) mice have recently been generated by gene targeting.12 13 14 These animals develop pronounced hypercholesterolemia on a normal chow diet, with chylomicron and very low lipoprotein remnant accumulation in plasma probably resulting from the abnormal receptor-mediated lipoprotein removal,15 16 an increase in atherogenic lipoprotein retention by matrix components, as well as slowing down of the reverse cholesterol transport from the arterial wall.17 18 Under these conditions, the mice develop lesions similar to those seen in humans, with foam cellrich fatty and fibrous lesions including both proliferating smooth muscle cells and calcium deposits. Bourassa et al19 recently reported the atheroprotective effect of 17ß-estradiol (E2) in this mouse model. However, these authors used a higher E2 dose than the substitutive one, defined as the lowest dose maintaining a normal uterine weight. Moreover, they did not consider that estrogen treatment in mice, in contrast to humans, decreases plasma HDL-cholesterol and apolipoprotein A-1 (apoA-1) concentrations,20 21 which may contribute to the development of an atherogenic lipoprotein profile.22 23 Indeed, previous reports have shown that C57BL/6 female mice on an atherogenic diet developed more extensive fatty streak formation than their male littermates,24 25 which was tentatively attributed to a higher level of HDL under the influence of testosterone.
The aim of the present study was therefore to investigate the influence of increasing doses of E2 on aortic lesion formation in apoE KO mice. Since it was expected that E2 would be unable to induce favorable changes in the blood lipoprotein profile, it was hypothesized that any measurable atheroprotective effect of E2 would be mediated at the level of the vascular wall. Testosterone treatment was also included to compare the effects on the lipoprotein profile.
| Methods |
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Serum Hormone Concentrations
Radioimmunoassay kits for 17ß-estradiol and testosterone were
used following manufacturer instructions (Sorin Biomedica). Hormone
levels were assayed for each individual mouse in a same series of
assays. The intra-assay coefficient of variability was 4.5% for
17ß-estradiol and 7.8% for testosterone. The assay sensitivity,
defined as 15% displacement of labeled tracer, was 0.5 pg
E2 and 12.5 pg testosterone.
Lipid Analyses
Serum total cholesterol concentrations were measured
using Boehringer-Mannheim Biochemicals enzymatic assay kits.
Serum lipoprotein separation was achieved by
ultracentrifugation micromethod as described by
Brousseau et al.26 HDL-cholesterol content was
also determined after selective precipitation of apoB-containing
lipoproteins with phosphotungstic acid/magnesium chloride
(Boehringer-Mannheim) according to Melhum et al.27
Comparative analysis of the two methods showed a highly
significant linear correlation coefficient (n=60, r=.836,
P<.001). Serum apoA-1 concentrations were measured in
castrated and 0.01- to 0.1-mg E2-treated animals by
immunonephelometry using mouse specific antibodies.27
Evaluation of Fatty Streak Formation
The lesions were estimated according to Paigen et
al.28 Briefly, the heart and ascending aorta were washed
in phosphate-buffered saline and fixed with phosphate-buffered
paraformaldehyde (4%, pH 7.4) for 24 hours. Each heart
was frozen on a cryostat mount with OCT compound (Tissue-Tek), and
stored at -70°C. One hundred sections of 10-µm thickness were
prepared from the top of the left ventricle, where the aortic valves
were first visible, up to a position in the aorta where the valve cusps
were just disappearing from the field. After drying for 2 hours, the
sections were stained with oil red O and counterstained with Mayer's
hematoxylin. Ten sections out of the 100, each separated by 90
µm, were used for specific morphometric evaluation of intimal lesions
using a computerized Biocom morphometry system. The first and most
proximal section to the heart was taken 90 µm distal to the
point where the aorta first becomes rounded. Lipid droplets <500
µm2 as well as those located in the media were excluded
from the measurements. The mean lesion size (expressed in
µm2) in these 10 sections was used to evaluate the lesion
size of each animal. The coded slides were examined blind in two
separate analyses by the same examiner and gave
consistent results (r=.94). Cellular composition was
also appreciated on successive sections analyzed either by oil
red O staining or by immunohistochemistry using the rat monoclonal
anti-mouse macrophages/monocytes (No. MCA519, Serotec) and IgG
rabbit anti-rat IgG FITC conjugate (Biosys).
Statistics
The results are presented as mean±SE. Because of a
large scatter in the individual values of lesion area, a logarithmic
transformation was performed and used for statistics and graphic
presentations. The significance of differences between
means was tested by using ANOVA comparison of the castrated mice
implanted with placebo or 0.01-, 0.05-, 0.1-, or 0.5-mg estradiol
pellets (ie, five groups for each sex). Bonferroni's post hoc test was
used to determine significant differences between two groups.
Differences between the castrated mice implanted with placebo and 7.5
mg testosterone, or intact mice, and between intact male and female
groups were also tested by using ANOVA. Correlations between different
parameters were analyzed using simple linear
regressions. The respective role of 17ß-estradiol treatment and of
sex on the lesions was analyzed by comparing the correlation
coefficients from the regression curves of lesion area in relation to
serum E2 (by the least squares method) and by a two-factor
ANOVA on the groups responsible for the dose-effect. A value of
P<.05 was considered as significant.
| Results |
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The mean body weight decreased significantly under the highest dose of E2 treatment in both males and females when compared with castrated animals. Weights were not different with the other doses of E2 and testosterone treatment.
As shown in Table 1
and 2
, total serum cholesterol was
higher in intact males than in intact females; it decreased under the
0.05- to 0.5-mg doses of E2 and testosterone treatment in
males and under the 0.5-mg E2 dose and testosterone in
females. LDL- and VLDL-cholesterol followed a similar
pattern although variations were not significantly different for
VLDL-cholesterol. In the placebo and E2-treated
groups, total cholesterol (r=-0.38,
P<.001 for the whole groups; r=-0.35,
P<.01 for females and r=-0.40,
P<.001 for males, respectively) and
LDL-cholesterol were negatively correlated with serum
E2 concentrations (r=-0.41, P<.0001
for the whole groups; r=-0.33, P<.03 for
females and r=-0.48, P<.001 for males,
respectively); a negative correlation was also observed between
VLDL-cholesterol and serum E2 concentrations in
the whole groups (r=-0.25, P<.02) and in males
(r=-0.28, P<.05) but not in females
(P=.14).
HDL-cholesterol increased significantly after ovariectomy
but not after orchidectomy; it was unaffected by testosterone treatment
and decreased significantly under E2 (0.05 to 0.5 mg)
treatment. In the placebo and E2-treated groups, a negative
correlation was observed between HDL-cholesterol and serum
E2 concentrations in the whole groups and in females
(r=-0.31, P<.001 and r=-0.33,
P<.05, respectively) but was of borderline significance in
males (P=.054). As shown in Fig 1
, serum apoA-1
concentrations also decreased maximally under the 0.05 mg
E2 dose in females but only under the 0.1 mg dose in
males. Indeed, serum
HDL-cholesterol and apoA-1 concentrations in the 0.01- to
0.1-mg E2-treated mice of either sex were highly correlated
(r=.80, P<.0001).
|
Effect of 17ß-Estradiol and Testosterone on Fatty Streak
Formation
As shown in Fig 2
, fatty streak areas were slightly higher in
intact and castrated females compared with intact and castrated males,
but the difference was not statistically
significant. The lesions decreased
in a dose-dependent manner in each sex (P<.0001). In
E2-treated females, significantly lower lesions were noted
with the 0.05-mg dose, and the maximal effect was reached at the dosage
of 0.1 mg and then plateaued at 0.5 mg. In males, a higher dose (0.1
mg) was required to significantly reduce the fatty streak formation,
which continued to decrease under 0.5 mg.
|
In the placebo and E2-treated groups, lesion area was
positively correlated with total serum cholesterol
(r=.43, P<.0001 for the whole groups;
r=.50, P<.001 and r=.37,
P<.01 for females and males, respectively) and with
LDL-cholesterol in the whole groups (r=.33,
P<.005) and males (r=.41, P<.02) but
not in females (P=.08). Lesion area was also positively
correlated with VLDL-cholesterol in the whole groups
(r=.24, P<.03) and with
HDL-cholesterol in the whole groups (r=0.22,
P<.05) and in females (r=0.35,
P<.03) but not in males (P=.63). Taking into
account that a maximal effect was reached at the dose of 0.1 mg
E2 in females and assigning a null value when the
E2 concentration was undetectable, a significant negative
high correlation was observed between lesion area and serum
E2 concentrations in the placebo and 0.01- to
0.1-mgtreated animals (r=- 0.70, P<.0001 for
the whole groups; r=-0.78, P<.0001 for females
and r=-0.65, P<.0001 for males). Furthermore, a
significant difference in the slopes (t=2.289, df=78,
P=.025) suggested an interaction of sex and E2
on lesion depth (Fig 3
). This
suggestion verified when a two-factor ANOVA was performed on the groups
given 0.01- to 0.1-mg pellets, which induced a dose-dependent decrease
in lesions. The dose-effect relationship differed between males and
females (P=.03), with no interaction between sex and dose
(P=.8).
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The lesions also decreased under testosterone treatment, although to a lesser extent than under E2 treatment.
| Discussion |
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In contrast to the relatively weak correlation with total
cholesterol and the different lipoprotein subfractions, a
highly significant correlation was observed between lesion area and
serum E2 levels, strongly suggesting a direct action of
E2 on cells of the vascular wall.
Endothelial cells could be involved through regulation
of permeability to lipoproteins, leukocyte adhesion and chemotaxis,
cytokine production, and/or superoxide anion
production, but the monocyte/macrophage lineage itself
could also be the site of this action. In fact, all vascular aortic
wall cells, including cells from the inflammatory/immune
system,31 are estrogen target cells, which express
estrogen receptors as well as aromatase, estradiol-17ß hydroxysteroid
dehydrogenase, and 17-ketoreductase enzyme
activities.32 33 34 In a recent communication, Rubanyi et al
reported that disruption of the estrogen receptor gene in mice
significantly modified vascular function, reducing basal release of
endothelium-derived nitric oxide and increasing smooth
muscle reactivity to KCl (10th International Congress of
Endocrinology. 1996. ORG18-1. Abstract). These data favor the
involvement of estrogen receptors in the mechanism of E2
action at the level of the vascular wall. The dose-response curves
obtained in the present study, show an "inhibitory
plasma concentration 50," inducing half a decrease in lesion area,
in the range of 0.05 nmol/L, which is consistent with
this hypothesis. This analysis also clearly shows that the
estrogen-dependent activities that mediate the atheroprotective effect
are recruited at higher hormonal concentrations than are needed by
other E2 target tissues such as uterus35 or
functions such as apoA-1 (compare Figs 1
and 2
), LDL (Table 2
), or VLDL
production and/or clearance rates.19 Although
E2 serum concentrations in this range have been reported by
some authors during the estrous cycle,36 37 such
concentrations are probably only reached during
pregnancy.35 Moreover, this sensitivity differs between
female and male animals, as shown in Figs 2
and 3
. In their recent
report, Bourassa et al19 also described the
atheroprotective effect of estrogens in this mouse model. Although both
sets of data are in agreement in general, the E2 doses used
(6 to 28 µg/d, generating plasma estradiol concentrations from
100 to 900 pg/mL) did not allow these authors to characterize
the peculiar tissue and sex specificity of the effect. The molecular
basis for such tissue and sex-specific responses to E2 is
not yet understood and may involve not only differences in chromatin
structure as well as estrogen receptor dynamics and
characteristics38 39 but also synergy between progesterone
and estrogen.40 With regard to humans, the incidence of
E2 on serum HDL-cholesterol and apoA-1
concentrations as well as absence of apoE probably make this mouse
model irrelevant for studies of lipoprotein metabolism.
However, this model is useful for definition of the target in the
vascular wall, and the data presented should be considered in
defining future clinical trials of postmenopausal replacement therapy
and possible pharmacological studies in males.
The lower but also significant atheroprotective effect of testosterone is more difficult to interpret. When administered in a continuous fashion, testosterone decreased total serum and LDL-cholesterol, suggesting an effect on lipoprotein production or metabolism. A direct effect at the level of the vascular wall, as a result of testosterone aromatization, should also be considered. Further work, using variable concentrations and non aromatizable androgens, should clarify these issues.
In conclusion, we confirm that 17ß-estradiol is effective in preventing the development of fatty streaks in female and male apoE KO mice. Moreover, this animal model allowed us to approach the respective roles of blood lipids and lipoproteins and the direct action on cells of the arterial wall and to define a peculiar tissue and sex specificity. This model is well adapted to characterization of the molecular mechanisms that mediate sex steroid hormone effects on the atherosclerosis process.
| Acknowledgments |
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Received December 31, 1996; accepted May 13, 1997.
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F. C. W. Wu and A. von Eckardstein Androgens and Coronary Artery Disease Endocr. Rev., April 1, 2003; 24(2): 183 - 217. [Abstract] [Full Text] [PDF] |
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J. B. Hodgin and N. Maeda Minireview: Estrogen and Mouse Models of Atherosclerosis Endocrinology, December 1, 2002; 143(12): 4495 - 4501. [Abstract] [Full Text] [PDF] |
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C. Pendaries, B. Darblade, P. Rochaix, A. Krust, P. Chambon, K. S. Korach, F. Bayard, and J.-F. Arnal The AF-1 activation-function of ERalpha may be dispensable to mediate the effect of estradiol on endothelial NO production in mice PNAS, February 19, 2002; 99(4): 2205 - 2210. [Abstract] [Full Text] [PDF] |
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A. Mortensen, V. Breinholt, T. Dalsgaard, H. Frandsen, S. T. Lauridsen, J. Laigaard, B. Ottesen, and J.-J. Larsen 17{beta}-Estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation in WHHL rabbits J. Lipid Res., May 1, 2001; 42(5): 834 - 843. [Abstract] [Full Text] |
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J. C. Escola-Gil, O. Jorba, J. Julve-Gil, F. Gonzalez-Sastre, J. Ordonez-Llanos, and F. Blanco-Vaca Pitfalls of Direct HDL-Cholesterol Measurements in Mouse Models of Hyperlipidemia and Atherosclerosis Clin. Chem., September 1, 1999; 45(9): 1567 - 1569. [Full Text] [PDF] |
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U. Brehme, B. Bruck, N. Gugel, M. Wehrmann, S. Hanke, G. Finking, F. W. Schmahl, and H. Hanke Aortic Plaque Size and Endometrial Response in Cholesterol-Fed Rabbits Treated With Estrogen Plus Continuous or Sequential Progestin Arterioscler. Thromb. Vasc. Biol., August 1, 1999; 19(8): 1930 - 1937. [Abstract] [Full Text] [PDF] |
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A. Maret, S. Clamens, I. Delrieu, R. Elhage, J.-F. Arnal, and F. Bayard Expression of the Interleukin-6 Gene Is Constitutive and Not Regulated by Estrogen in Rat Vascular Smooth Muscle Cells in Culture Endocrinology, June 1, 1999; 140(6): 2876 - 2882. [Abstract] [Full Text] |
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M. M. Marsh, V. R. Walker, L. K . Curtiss, and C. L. Banka Protection against atherosclerosis by estrogen is independent of plasma cholesterol levels in LDL receptor-deficient mice J. Lipid Res., May 1, 1999; 40(5): 893 - 900. [Abstract] [Full Text] |
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