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Department of Internal Medicine, The Cardiovascular Center, and Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The objectives of the present study were
to 1) examine mechanisms involved in
endothelium-dependent responses of coronary arteries from normal mice
and 2) determine whether vascular
responses of coronary arteries are altered in two genetic models of
hypercholesterolemia [apolipoprotein E (apoE)-deficient mice
(apoE 
/) and combined apoE and low-density lipoprotein
receptor (LDLR)-deficient mice (apoE + LDLR /)].
Plasma cholesterol levels were higher in both apoE / and
apoE + LDLR / compared with normal mice on normal and
high-cholesterol diets (normal chow: normal 110 ± 5 mg/dl, apoE
/ 680 ± 40 mg/dl, apoE + LDLR / 810 ± 40 mg/dl; high-cholesterol chow: normal 280 ± 60 mg/dl, apoE
/ 2,490 ± 310 mg/dl, apoE + LDLR /
3,660 ± 290 mg/dl). Coronary arteries from normal (C57BL/6J), apoE
/, and apoE + LDLR / mice were isolated and
cannulated, and diameters were measured using videomicroscopy. In
normal mice, vasodilation in response to ACh and serotonin was markedly
reduced by 10 µM
N
-nitro-L-arginine (an inhibitor
of nitric oxide synthase) or 20 µM
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ; an inhibitor of soluble guanylate cyclase). Vasodilation to
nitroprusside, but not papaverine, was also inhibited by ODQ. Dilation
of arteries from apoE / and apoE + LDLR /
mice on normal diet in response to ACh was similar to that observed in
normal mice. In contrast, dilation of arteries in response to serotonin
from apoE / and apoE + LDLR / mice was
impaired compared with normal. In arteries from both apoE
/ and apoE + LDLR / mice on
high-cholesterol diet, dilation to ACh was decreased. In apoE + LDLR
/ mice on high-cholesterol diet, dilation of coronary
arteries to nitroprusside was increased. These findings suggest that
dilation of coronary arteries from normal mice in response to ACh and
serotonin is dependent on production of nitric oxide and activation of
soluble guanylate cyclase. Hypercholesterolemia selectively impairs
dilator responses of mouse coronary arteries to serotonin. In the
absence of both apoE and the LDL receptor, high levels of cholesterol result in a greater impairment in coronary endothelial function.
coronary artery; acetylcholine; serotonin; gene-targeted mice; endothelium; nitric oxide; soluble guanylate cyclase
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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PREVIOUS STUDIES of vascular reactivity in experimental
models of atherosclerosis have generally relied on diet-induced
hyperlipidemia (10, 13, 14, 34). Watanabe rabbits, a genetic model of hyperlipidemia and atherosclerosis, have also been studied (36, 37).
Because both genetics and diet may play a role in the development of
vascular disease, models incorporating both are advantageous. Recent
development of murine models with known defects in cholesterol metabolism provide potentially valuable models for studies of the
effects of hypercholesterolemia on vascular biology. Mice deficient in
apolipoprotein E (apoE /) (2, 25, 39) or combined apoE
and low-density lipoprotein receptor (LDLR)-deficient mice (apoE + LDLR
/) (15) develop spontaneous hypercholesterolemia and
atherosclerotic lesions similar to lesions that develop in humans (31,
32, 38).
Several studies have demonstrated that atherosclerosis is associated
with impaired endothelium-dependent relaxation in dietary-induced models of atherosclerosis in animals (10, 13, 14, 34) and in humans
with arterial atherosclerosis (12, 30). Studies from our laboratory
have demonstrated that abnormal vascular function in aorta from apoE + LDLR / mice correlated with the presence of
atherosclerotic lesions (1). Vascular function was greatly impaired in
proximal segments of aorta from combined apoE + LDLR /
mice, whereas in distal segments, with minimal evidence of atherosclerotic lesions, endothelium-dependent relaxation to ACh was
normal. In contrast, in apoE-deficient mice with similar levels of
plasma cholesterol, intimal lesions were minimal and vascular function
was not impaired. Atherosclerosis appears to be
accelerated in apoE + LDLR-deficient mice compared with apoE deficiency
alone, and this suggests that absence of LDLR and the resulting
increased levels of plasma LDL contribute to the development of disease and abnormal vascular function (1).
In the present study, we examined vascular reactivity in the coronary
circulation of normal mice and two genetic models of hypercholesterolemia (apoE / and apoE + LDLR
/ mice). Mechanisms that mediate endothelium-dependent
relaxation in coronary arteries from normal mice are not known. Before
alteration in vascular reactivity could be assessed in models of
disease, we felt it was important to begin to understand mechanisms
involved in the regulation of reactivity in normal arteries. Thus the
first goal of this study was to examine mechanisms that mediate
responses of coronary arteries from normal mice to ACh and serotonin
(5-HT). The second goal of this study was to compare responses of
coronary arteries from apoE / and apoE + LDLR
/ mice to determine if genetic deficiency of apoE or apoE
and LDLR receptors is associated with vascular dysfunction in these
murine models. In addition, we determined whether the effects of
genetically induced hypercholesterolemia are exacerbated by a
high-cholesterol diet.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals.
The animal protocol used in these experiments was reviewed and approved
by the University of Iowa Animal Care and Use Committee. Three groups
of mice were studied: normal mice (C57BL/6J), homozygous apoE-deficient
mice (apoE /), and homozygous apoE and LDL
receptor-deficient mice (apoE + LDLR /). Mice were a
third- or fourth-generation hybrid from a 129 × C57BL/6J
background from a colony at The Jackson Laboratory. Both male and
female mice were fed regular chow or a high-cholesterol diet
supplemented with 1% cholesterol (wt/wt) for 10 wk beginning at 5 wk
of age. Water was available ad libitum. Ages of mice in the different
groups were similar (regular chow: normal 16 ± 1 wk, apoE
/ 17 ± 1 wk, apoE + LDLR / 17 ± 1 wk; high-cholesterol chow: normal 23 ± 1 wk, apoE
/ 21 ± 1 wk, apoE + LDLR / 29 ± 1 wk). Levels of plasma cholesterol and fast protein liquid
chromatography fractions were determined by colorimetric enzymatic
assays (Boehringer Mannheim kit no. 126012). After an overnight fast,
100-µl samples of mouse plasma were withdrawn, fractionated on a
Superose 6 column (Pharmacia) with 10 mmol/l Tris-buffered saline (pH
8.0), pumped at 0.5 ml/min, and collected in 0.5-ml fractions as
previously described (4).
General preparation. Mice were anesthetized with Avertin (240 mg/kg) and heparinized intraperitoneally. A sample of blood was drawn from caudal vena cava for measurement of total serum cholesterol. Hearts were rapidly removed and placed in cold Krebs buffer of the following composition (in mM/l): 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 25 NaHCO3, and 11.1 glucose. Epicardial arteries (62-160 µm in diameter) were isolated from myocardium under a microscope (×40), placed in a Plexiglas organ chamber filled with cold Krebs solution, cannulated with dual micropipettes, and secured with 10-0 monofilament suture. The organ chamber (20 ml) was continuously circulated with Krebs solution bubbled with 20% O2, 5% CO2, and 75% N2. Vessels were pressurized to 20 mmHg under no-flow conditions using two reservoirs filled with Krebs solution. Images of microvessels were displayed on a video monitor using a Leitz microscope (×100) connected to a Hitachi camera. An electronic video dimension analyzer (Living Systems Instrumentation, Burlington, VT) continuously measured luminal diameter. The distending pressure of the vessels was measured with a pressure transducer connected to a side arm of the cannula connected to one of the micropipettes. Vessels were allowed to equilibrate for 60 min before study. Viability of the vessels was assessed as a minimum of 30-50% constriction from a resting diameter in response to 100 mM KCl.
Protocols.
Vessel segments were preconstricted with the thromboxane mimetic
9,11-dideoxy-11a,9a-epoxy-methanoprostaglandin
F2
(U-46619; ~7-17 × 10
8 M) to
30-60% of the initial vessel diameter. Baseline diameters were
the diameters of arteries before preconstriction with U-46619. In
coronary arteries from C57BL/6J mice, cumulative dose-response curves
to ACh
(109-105
M), 5-HT
(109-105
M in presence of 106 M
ketanserin), and nitroprusside
(109-105
M) were performed. To determine the role of nitric oxide and soluble
guanylate cyclase in responses of coronary arteries to ACh, we
performed dose-response curves to ACh and 5-HT in separate groups of
arteries in the presence of
N-nitro-L-arginine
(L-NNA; 10 µM) to inhibit
nitric oxide synthase (NOS) and
1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
(ODQ; 10 µM) to inhibit soluble guanylate cyclase. Responses to 5-HT
were also tested in the presence of
L-NNA or ODQ to determine the
role of nitric oxide and soluble guanylate cyclase. The concentrations of L-NNA and ODQ were chosen
based on previous experiments (1, 6, 35).
5-2 × 104 M) and
nitroprusside
(109-105
M, a nitric oxide donor) were measured in the presence of ODQ.
In coronary arteries from apoE / and apoE + LDLR
/ on normal and high-cholesterol diet, cumulative
dose-response curves to ACh
(109-105
M), 5-HT
(109-105
M in presence of 106 M
ketanserin, a 5-HT2 receptor
antagonist), and sodium nitroprusside (109-105
M) were performed.
Drugs. Avertin was made by mixing 2,2,2-tribromoethanol (0.25 g) and 2-methyl-2-butanol (0.5 ml) in distilled water (20 ml). U-46619 was obtained from Biomol Research Laboratories and dissolved in 100% ethanol. ACh, nitroprusside, 5-HT, L-NNA, and ketanserin were obtained from Sigma (St. Louis, MO) and dissolved in distilled water. All concentrations are final molar concentrations in the organ chamber. All agents were dissolved in distilled water.
Statistical analysis. Data are presented as percent change in diameter from the preconstricted diameter and are means ± SE. One vessel was obtained per mouse, and n represents the number of mice per group. One dose-response curve was performed per vessel. Comparisons were made using a one-way ANOVA with repeated measures followed by Student-Newman-Keuls test to detect individual differences. ED50 values were calculated. Maximal responses, ED50 values, and plasma cholesterol levels were compared by Student's t-test. P < 0.05 was considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Responses of coronary arteries from normal mice to ACh.
ACh produced dose-dependent dilation of coronary arteries from normal
mice (baseline diameter 119 ± 8 µm,
n = 10, Fig.
1). The maximal dilation in response to ACh
was 45 ± 7%. Dilation in response to ACh was inhibited
substantially by L-NNA (10 µM, n = 5) and ODQ (10 µM,
n = 3, Fig. 1), suggesting that the
response is dependent on formation of nitric oxide and activation of
guanylate cyclase.
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Responses of coronary arteries from normal mice to 5-HT.
We examined responses of coronary arteries to 5-HT, a second
endothelium-mediated vasodilator. Responses to 5-HT were measured in
the presence of ketanserin to separate endothelium-mediated effects
from direct effects on vascular muscle (due to activation of
5-HT2 receptors). In the presence
of ketanserin, 5-HT produced dose-dependent dilation of coronary
arteries (baseline diameter 116 ± 12 µm,
n = 6, Fig.
2). Dilation to 5-HT was inhibited by L-NNA (10 µM,
n = 7, Fig. 2) and ODQ (10 µM,
n = 5, Fig. 2). These findings suggest
that in mouse coronary arteries, dilation to 5-HT is mediated by
release of nitric oxide and stimulation of soluble guanylate cyclase.
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Response of coronary arteries from normal mice to nitroprusside and
papaverine.
To determine whether effects of ODQ were selective for responses
mediated through activation of guanylate cyclase, we measured responses
to papaverine, a nonspecific vasodilator, in the absence and presence
of ODQ. Papaverine produced dose-dependent dilation of coronary
arteries (n = 6) that was not altered
by ODQ (n = 5, Fig.
3). As part of these experiments, we also
examined the effects of ODQ on responses to nitroprusside.
Nitroprusside produced dose-dependent dilation of coronary arteries
from normal mice (n = 5, Fig.
4). Dilation to nitroprusside was markedly
reduced by ODQ (n = 5, Fig. 4) but not
L-NNA
(n = 6, Fig. 4).
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Responses of apoE / and apoE + LDLR / mice to ACh and
5-HT.
Next, we studied effects of hyperlipidemia on responses of coronary
arteries from apoE and apoE + LDLR / mice compared with arteries from normal mice. On normal chow, dilation in response to ACh
was similar in control, apoE / (baseline diameter 120 ± 10 µm, n = 9), and apoE + LDLR
/ mice (baseline diameter 117 ± 4 µm,
n = 6, Fig.
5A).
Maximal responses to ACh were not altered in either apoE
/ or apoE + LDLR / mice (normal, 49 ± 7%; apoE /, 45 ± 7%; apoE + LDLR /,
40 ± 5%). In contrast to animals on normal diet, dilation in
response to ACh of coronary arteries from apoE /
(baseline diameter 111 ± 11 µm,
n = 6) and apoE + LDLR /
mice (baseline diameter 127 ± 13 µm,
n = 7) on high-cholesterol diet was
less than dilation of coronary arteries from normal mice (Fig.
5B). Maximal dilation to ACh was
decreased in arteries from apoE / and apoE + LDLR
/ mice (normal, 49 ± 7%; apoE /, 32 ± 5%; apoE + LDLR /, 16 ± 6%;
P < 0.05 vs. normal). The response of coronary arteries to ACh from normal mice on high-cholesterol diet
was similar to mice on normal diet (maximal dilation 55 ± 4%,
n = 3).
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/ (baseline
diameter 111 ± 7 µm, n = 6) and
apoE + LDLR / mice (baseline diameter 117 ± 5 µm,
n = 6) on normal diet in response to
5-HT was reduced compared with arteries from normal mice (Fig.
6). The decreased dilation to 5-HT of
arteries from apoE / and apoE + LDLR / mice
was in marked contrast to the response to ACh in arteries from the same
mice. Maximal dilation of arteries to 5-HT was decreased in apoE
/ and apoE + LDLR / compared with normal
mice (normal, 75 ± 7%; apoE /, 43 ± 11%; apoE + LDLR /, 44 ± 6%; P < 0.05 vs. normal).
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Responses of apoE / and apoE + LDLR / mice to
nitroprusside.
To determine whether the decreased dilation to ACh and 5-HT was due to
a nonspecific impairment of vascular muscle function in apoE
/ and apoE + LDLR / mice, we examined
responses to the endothelium-independent dilator nitroprusside.
Nitroprusside produced similar dilation of coronary arteries from
normal, apoE / (n = 4),
and apoE + LDLR / mice
(n = 4) on normal diet
(ED50 normal, 6.8 ± 0.3; apoE
/, 6.7 ± 0.3; apoE + LDLR /, 7.2 ± 0.3, Fig.
7A).
Dilation to 105 M
nitroprusside was also similar in all groups (normal, 65 ± 9%;
apoE /, 70 ± 8%; apoE + LDLR /, 68 ± 11%). Dilation to nitroprusside was shifted to the left in
arteries from apoE + LDLR / mice on high-cholesterol
(n = 6) compared with normal diet
(ED50 normal, 6.8 ± 0.3; apoE
/, 6.8 ± 0.1; apoE + LDLR /, 7.5 ± 0.1; P < 0.05 vs. normal, Fig.
7B). Maximal dilation to
nitroprusside was similar in arteries from all groups on
high-cholesterol diet (normal, 65 ± 9%; apoE /, 71 ± 9%; apoE + LDLR /, 69 ± 7%).
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Plasma cholesterol levels.
The total plasma cholesterol levels were higher in apoE /
(680 ± 40 mg/dl, n = 19)
and apoE + LDLR / mice (810 ± 40 mg/dl, n = 16) compared with normal
mice (110 ± 5 mg/dl, P < 0.05 vs. apoE / and apoE + LDLR /,
n = 16) on normal chow. Levels of plasma cholesterol were higher in each group on high-cholesterol compared with normal chow (normal, 280 ± 60 mg/dl,
n = 7; apoE /, 2,490 ± 310 mg/dl, n = 11; apoE + LDLR
/, 3,660 ± 290 mg/dl, n = 16;
P < 0.05 vs. normal chow). We and
others have previously published that normal mice do not have a
prominent peak of cholesterol-containing particles in the very low
density lipoprotein (VLDL) and LDL ranges when measured by fast protein
liquid chromatography. The most prominent fraction of
cholesterol is in the high-density lipoprotein (HDL) range
(1). By comparison, the apoE / and apoE + LDLR / mice have a prominent fraction of cholesterol in the
VLDL and LDL ranges (1). The apoE + LDLR / mice have an
additional prominent peak of LDL particles (1, 15).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study is the first to examine mechanisms that mediate responses of coronary arteries from normal mice to ACh, 5-HT, and nitroprusside. Coronary arteries from normal mice dilate to ACh, 5-HT, nitroprusside, and papaverine. Vasodilation in response to ACh and 5-HT is inhibited by both L-NNA and ODQ. Dilation to nitroprusside, a nitric oxide donor, is also inhibited by ODQ. These data suggest that dilation of normal murine coronary arteries to ACh and 5-HT is mediated by production of nitric oxide and activation of soluble guanylate cyclase.
This study also demonstrated that dilation of coronary arteries from genetic models of hypercholesterolemia is selectively impaired to 5-HT, but not ACh, unless mice are fed a high-cholesterol diet. These results differ from a previous study in which abnormal responses of the aorta to ACh in genetic models of hypercholesterolemia were correlated with the presence of atherosclerotic lesions (1). In that study, endothelium-dependent relaxation was intact in vessels with minimal disease. Another interesting finding in the current study is that responses to nitroprusside were enhanced in mice on a high-cholesterol diet.
Reactivity of normal coronary arteries from mice.
Understanding mechanisms that regulate vascular tone in coronary
vessels from normal mice produces a foundation for subsequent studies
of murine models with specific genetic alterations.
Endothelium-dependent relaxation to ACh can be mediated by nitric
oxide, endothelium-derived hyperpolarizing factor, or prostacyclin,
depending on the species, organ, or location of the vessel within the
vascular tree (7, 9, 19, 29). Mechanisms that mediate responses to ACh
and 5-HT in the mouse coronary circulation were unknown previously. Results of the present study suggest that dilation of mouse coronary arteries in response to ACh and 5-HT is mediated primarily by nitric
oxide. In humans with no angiographic evidence of coronary artery
disease, responses of both large coronary arteries and resistance
vessels to ACh (5) and bradykinin (17) are mediated by a similar
mechanism because responses to these stimuli were inhibited markedly by
N-nitro-L-arginine methyl
ester. However, in the presence of inhibitors of NOS,
dilation to endothelium-dependent agonists in the present study in mice
and previous studies in humans (5, 17) were not completely inhibited,
suggesting that other mechanisms may in part contribute to the response.
Effect of hypercholesterolemia on vascular reactivity. Several studies have demonstrated abnormal vascular reactivity in diet-induced animal models and humans with atherosclerosis (10, 13, 14, 34). Mechanisms that may be involved in the decreased endothelium-dependent response in mice with high cholesterol are unknown. On the basis of previous studies, we could speculate that decreased nitric oxide-mediated responses may be due to an increased degradation of nitric oxide, decreased synthesis and/or release of nitric oxide, or impaired responses of vascular smooth muscle to nitric oxide. It seems unlikely that reactivity of vascular smooth muscle is decreased, because the dilation to nitroprusside was similar in coronary arteries from normal and hypercholesterolemic mice on normal chow and even enhanced in arteries from mice on a high-cholesterol diet. Impaired dilation to endothelium-dependent agents may be due to increased degradation and/or inactivation of nitric oxide by superoxide anion (22, 24). Increased production of superoxide has been reported in several studies, and endothelium-dependent responses in atherosclerotic arteries can be restored toward normal by treatment with superoxide dismutase (23, 24).
In the present study, dilation to 5-HT was impaired in coronary arteries from apoE and apoE + LDLR/ mice on normal chow, whereas dilation to ACh was normal in arteries from the same mice. Abnormal dilation to ACh was evident in coronary arteries from mice
only when they were on a high-cholesterol diet. Reasons for the
difference in responses to 5-HT and ACh in arteries from mice on normal
chow are unclear but may be related to differences in mechanisms of
agonist-mediated release of nitric oxide. Dilation to 5-HT seems to
involve activation of a pertussis toxin-sensitive Gi protein (8), whereas ACh
activates multiple G proteins (27). Hypercholesterolemia may
selectively impair dilation to pertussis toxin-sensitive
Gi proteins to a greater extent
than other G protein-mediated responses (33), making responses to 5-HT
more abnormal in atherosclerosis. These data suggest that responses to
5-HT may be a more sensitive indicator of abnormal vascular function.
ApoE mediates cellular uptake of cholesterol from serum lipoprotein
particles such as VLDL, intermediate density lipoprotein (IDL), and
-VLDL through interactions with LDLR (21). Interactions of apoE with
circulating lipoproteins result in a decreased plasma cholesterol
concentration. In murine models of apoE or LDLR deficiency, plasma
VLDL, IDL, and LDL are all increased, and atherosclerotic lesions
characteristic of those seen in humans develop. Clinically, deficiency
of apoE or LDL receptors leads to hypercholesterolemia and
atherosclerosis although the cholesterol characteristics are different. ApoE deficiency leads to elevated remnant
cholesterol fraction (type III hyperlipoproteinemia) (12, 21), and LDL deficiency leads to an increase in serum LDL (familial
hypercholesterolemia) (3). ApoE deficiency results in elevated levels
of VLDL and IDL and decreased HDL (31, 39, 1), whereas deficiency of both apoE and LDL receptors results in an even higher serum cholesterol with a prominent increase in LDL. It seems possible that differences in
vascular responses in apoE / and apoE + LDLR
/ mice may be related to differences in lipid profile in
the two models.
Recent studies have suggested that vascular reactivity in models of
hypercholesterolemia is altered, at least in part, after oxidation of
LDL and generation of reactive oxygen species (11, 16, 18, 26).
Oxidized LDL is a potent inhibitor of endothelium-dependent relaxation.
The present study suggests that in genetic models of
hypercholesterolemia, alterations in coronary vascular reactivity are
selectively altered. In coronary arteries from apoE / and apoE + LDLR / mice on a normal diet, responses of
coronary arteries to 5-HT are impaired, whereas responses to ACh are
not different. Explanations for these differences in responses to 5-HT
versus ACh may reflect differences in specific receptors, the role of G
protein in the responses, or other compensatory vasodilator pathways in
the presence of atherosclerosis.
In summary, these findings suggest that in normal mice, dilation of
coronary arteries to ACh and 5-HT are primarily mediated by release of
nitric oxide and activation of soluble guanylate cyclase. In two
genetic models of hypercholesterolemia, dilation to 5-HT was impaired,
whereas dilation to ACh was only impaired in mice with very high levels
of serum cholesterol. These studies of vascular reactivity in normal
and hypercholesterolemic mice models demonstrate the potential use of
murine models with defects in expression of specific gene products to
study mechanisms involved in regulation of coronary vascular
reactivity. In addition, differences in reactivity of coronary arteries
in the present study compared with responses in other vascular beds
demonstrate the need to perform studies comparing mechanisms of
reactivity in multiple vascular tissue types in these models.
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ACKNOWLEDGEMENTS |
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We acknowledge the technical help of Mark Andracki and Kristen Rummelhart.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-39050 (K. G. Lamping), HL-49264 (D. A. Chappell), and HL-38901, National Institute of Neurological Disorders and Stroke Grant NS-24621 (F. M. Faraci), and the Dept. of Veterans Affairs. K. G. Lamping and F. M. Faraci are Established Investigators of the American Heart Association.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: K. G. Lamping, Assistant Professor, Medical Services (111), VA Medical Center, Iowa City, IA 52246 (E-mail: kathryn-lamping{at}uiowa.edu).
Received 18 May 1998; accepted in final form 5 January 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1.
Bonthu, S.,
D. D. Heistad,
D. A. Chappell,
K. G. Lamping,
and
F. M. Faraci.
Atherosclerosis, vascular remodeling, and impairment of endothelium-dependent relaxation in genetically altered hyperlipidemic mice.
Arterioscler. Thromb. Vasc. Biol.
17:
2333-2340,
1997
2.
Breslow, J. L.
Mouse models of atherosclerosis.
Science
272:
685-688,
1996[Abstract].
3.
Brown, M. S.,
J. R. Faust,
and
J. L. Goldstein.
Role of the low density lipoprotein receptor in regulating the content of free and esterified cholesterol in human fibroblasts.
J. Clin. Invest.
55:
783-793,
1975.
4.
De Silva, H. V.,
J. Mas-Oliva,
J. M. Taylor,
and
R. W. Mahley.
Identification of apolipoprotein B-100 low density lipoproteins, apolipoprotein B-48 remnants, and apolipoprotein E-rich high density lipoproteins in the mouse.
J. Lipid Res.
35:
1297-1310,
1994[Abstract].
5.
Egashira, K.,
Y. Katsuda,
M. Mohri,
T. Kuga,
T. Tagawa,
T. Kubota,
Y. Hirakawa,
and
A. Takeshita.
Role of endothelium-derived nitric oxide in coronary vasodilatation induced by pacing tachycardia in humans.
Circ. Res.
79:
331-335,
1996
6.
Faraci, F. M.,
C. D. Sigmund,
E. G. Shesely,
N. Maeda,
and
D. D. Heistad.
Responses of carotid artery in mice deficient in expression of the gene for endothelial NO synthase.
Am. J. Physiol.
274 (Heart Circ. Physiol. 43):
H564-H570,
1998
7.
Feletou, M.,
and
P. M. Vanhoutte.
Endothelium-dependent hyperpolarization of canine coronary smooth muscle.
Br. J. Pharmacol.
93:
515-524,
1988[Medline].
8.
Flavahan, N. A.,
H. Shimokawa,
and
P. M. Vanhoutte.
Pertussis toxin inhibits endothelium-dependent relaxations to certain agonists in porcine coronary arteries.
J. Physiol. (Lond.)
408:
549-560,
1989
9.
Forstermann, U.,
A. Mulsch,
E. Bohme,
and
R. Busse.
Stimulation of soluble guanylate cyclase by an acetylcholine-induced endothelium-derived factor from rabbit and canine arteries.
Circ. Res.
58:
531-538,
1986
10.
Freiman, P. C.,
G. G. Mitchell,
D. D. Heistad,
M. L. Armstrong,
and
D. G. Harrison.
Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates.
Circ. Res.
58:
783-789,
1986
11.
Galle, J.,
A. Mulsch,
R. Busse,
and
E. Bassenge.
The effects of native and oxidized low-density lipoproteins on the formation and inactivation of endothelium-derived relaxing factor.
Arterioscler. Thromb.
11:
198-203,
1991
12.
Ghiselli, G. E.,
E. J. Schaefer,
P. Gascon,
and
H. B. Brewer.
Type III hyperlipidemia associated with apolipoprotein E deficiency.
Science
214:
1239-1241,
1981
13.
Heistad, D. D.,
M. L. Armstrong,
M. L. Marcus,
D. J. Piegors,
and
A. L. Mark.
Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys.
Circ. Res.
54:
711-718,
1984
14.
Henry, P. D.,
and
M. Yokoyama.
Supersensitivity of atherosclerotic rabbit aorta to ergonovine.
J. Clin. Invest.
66:
306-313,
1980.
15.
Ishibashi, S.,
J. Herz,
N. Maeda,
J. L. Goldstein,
and
M. S. Brown.
The two-receptor model of lipoprotein clearance: test of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E or both proteins.
Proc. Natl. Acad. Sci. USA
91:
4431-4435,
1994
16.
Jacobs, M.,
F. Plane,
and
K. R. Bruckdorfer.
Native and oxidized LDL have different inhibitory effects on endothelium derived relaxing factor in the rabbit aorta.
Br. J. Pharmacol.
100:
21-26,
1990[Medline].
17.
Kuga, T.,
M. Mohri,
K. Egashira,
Y. Hirakawa,
T. Tagawa,
H. Shimokawa,
and
A. Takeshita.
Bradykinin-induced vasodilation of human coronary arteries in vivo: role of nitric oxide and angiotensin-converting enzyme.
J. Am. Coll. Cardiol.
30:
108-112,
1997[Abstract].
18.
Kugiyama, K.,
S. A. Kerns,
J. D. Morrisett,
R. Roberts,
and
P. D. Henry.
Impairment of endothelium dependent arterial relaxation by lysolecithin in modified low-density lipoproteins.
Nature
344:
160-162,
1990[Medline].
19.
Lamontagne, D.,
A. Konig,
E. Bassenge,
and
R. Busse.
Prostacyclin and nitric oxide contribute to the vasodilator action of acetylcholine and bradykinin in the intact rabbit coronary bed.
J. Cardiovasc. Pharmacol.
20:
652-657,
1992[Medline].
20.
Liao, J. K.,
M. A. Bettmann,
T. Sandor,
J. I. Tucker,
S. M. Coleman,
and
M. A. Creager.
Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in humans with atherosclerosis.
Circ. Res.
68:
1027-1034,
1991
21.
Mahley, R. W.
Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.
Science
240:
622-630,
1988
22.
Minor, R. L.,
P. R. Myers,
R. Guerra,
J. N. Bates,
and
D. H. Harrison.
Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta.
J. Clin. Invest.
86:
2109-2116,
1990.
23.
Mugge, A.,
J. H. Elwell,
T. E. Peterson,
and
D. G. Harrison.
Release of intact endothelium-derived relaxing factor depends on endothelial superoxide dismutase activity.
Am. J. Physiol.
260 (Cell Physiol. 29):
C219-C225,
1991
24.
Mugge, A.,
J. H. Elwell,
T. E. Peterson,
T. G. Hofmeyer,
D. D. Heistad,
and
D. H. Harrison.
Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits.
Circ. Res.
69:
1293-1300,
1991
25.
Nakashima, Y.,
A. S. Plump,
E. W. Raines,
J. L. Breslow,
and
R. Ross.
ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree.
Arterioscler. Thromb.
14:
133-140,
1994
26.
Napoli, C.,
R. Paterno,
F. M. Faraci,
H. Taguchi,
A. Postiglione,
and
D. D. Heistad.
Mildly oxidized low-density lipoprotein impairs responses of carotid but not basilar artery in rabbits.
Stroke
28:
2266-2272,
1997
27.
Offermanns, S.,
D. Wieland,
D. Homann,
J. Sandmann,
E. Bombien,
K. Spicher,
G. Schultz,
and
K. H. Jakobs.
Transfected muscarinic acetylcholine receptors selectively couple to Gi-type G proteins and Gq/11.
Mol. Pharmacol.
45:
890-898,
1994[Abstract].
28.
Olesen, S. P.,
J. Drejer,
O. Axelsson,
P. Moldt,
L. Bnag,
J. E. Nielsen-Kudsk,
R. Busse,
and
A. Mulsch.
Characterization of NS 2028 as a specific inhibitor of soluble guanylyl cyclase.
Br. J. Pharmacol.
123:
299-309,
1998[Medline].
29.
Palmer, R. M. J.,
A. G. Ferrige,
and
S. Moncada.
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor.
Nature
327:
524-525,
1987[Medline].
30.
Panza, J. A.,
P. R. Casino,
C. M. Kilcoyne,
and
A. A. Quyyumi.
Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension.
Circulation
87:
1468-1474,
1993
31.
Plump, A. S.,
J. D. Smith,
T. Hayek,
K. Aalto-Serala,
A. Walsh,
J. G. Verstuyft,
E. M. Rubin,
and
J. L. Breslow.
Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.
Cell
71:
343-353,
1992[Medline].
32.
Reddick, R. L.,
S. H. Zhang,
and
N. Maeda.
Atherosclerosis in mice lacking apo E: evaluation of lesional development and progression.
Arterioscler. Thromb.
14:
141-147,
1994
33.
Shimokawa, H.,
N. A. Flavahan,
and
P. M. Vanhoutte.
Loss of endothelial pertussis toxin-sensitive G protein in atherosclerotic porcine coronary arteries.
Circulation
83:
652-660,
1991
34.
Shimokawa, H.,
H. Tomoike,
S. Nabeyama,
H. Yamamoto,
H. Araki,
M. Nakamura,
Y. Ishii,
and
K. Tanaka.
Coronary artery spasm induced in atherosclerotic miniature swine.
Science
221:
560-561,
1983
35.
Sobey, C. G.,
and
F. M. Faraci.
Effects of a novel inhibitor of guanylate cyclase on dilator responses of mouse cerebral arterioles.
Stroke
28:
837-843,
1997
36.
Tagawa, H.,
H. Tomoike,
and
M. Nakamura.
Putative mechanisms of the impairment of endothelium-dependent relaxation of the aorta with atheromatous plaque in heritable hyperlipidemic rabbits.
Circ. Res.
68:
330-337,
1991
37.
Taguchi, H.,
F. M. Faraci,
T. Kitazono,
and
D. D. Heistad.
Relaxation of the carotid artery to hypoxia is impaired in Watanabe heritable hyperlipidemic rabbits.
Arterioscler. Thromb. Vasc. Biol.
15:
1641-1645,
1995
38.
Tangirala, R. K.,
E. M. Rubin,
and
W. Palinski.
Quantitation of atherosclerosis in murine models: correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice.
J. Lipid Res.
36:
2320-2328,
1995[Abstract].
39.
Zhang, S. H.,
R. L. Reddick,
J. A. Piedrahita,
and
N. Maeda.
Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E.
Science
258:
468-471,
1992
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