© 1997 American Heart Association, Inc.
Articles |
Comparison of Aorta and Pulmonary Artery
II. LDL Transport and Metabolism Correlate With Susceptibility to Atherosclerosis
From the Department of Pathology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.
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Abstract The pulmonary artery and the aorta are similarly susceptible to atherosclerosis in rabbits. However, the mechanism(s) that accounts for this is not yet known. This study investigated the hypothesis that one or more aspects of arterial low-density lipoprotein (LDL) transport and metabolism might explain the similar susceptibility of the aortic arch and pulmonary artery to atherosclerosis and the increased susceptibility of these arterial regions compared with the descending thoracic aorta. We determined permeability to LDL, rates of LDL degradation, and concentrations of undegraded LDL for the intima-media of normal rabbits and those fed cholesterol for
8 days.
Intima-media permeability did not differ between corresponding
arterial regions of normal rabbits and rabbits fed
cholesterol for 8 days and was similar for the aortic arch
and pulmonary artery. Rates of LDL degradation and
concentrations of undegraded LDL for the intima-media were influenced
by cholesterol feeding. These measures were reduced in
fractional terms but increased in absolute terms as a result of
hypercholesterolemia, without differences
between corresponding parameters for the pulmonary
artery and aortic arch. However, permeability to LDL, rates of LDL
degradation, and concentrations of undegraded LDL were increased for
the intima-media of the aortic arch compared with the descending
thoracic aorta. Similar, although not always significant, trends were
evident for the comparison of the pulmonary artery and
descending thoracic aorta. Differences in LDL transport and
metabolism and changes after feeding
cholesterol for 8 days parallel the relative susceptibility
to atherosclerosis for the three arterial
regions studied. These results support the role of arterial
LDL transport and metabolism in atherogenesis and
potentially provide a mechanistic explanation for the differences in
susceptibility to atherosclerosis for these three
arterial regions.
Key Words: atherosclerosis • aorta • pulmonary artery • LDL permeability • LDL metabolism
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In human beings, the pulmonary artery is resistant to atherosclerosis, except in circumstances of pulmonary hypertension.1 In contrast, in rabbits2 3 4 5 6 7 8 9 and mice,10 atherosclerosis develops in the pulmonary artery in the absence of known hypertension. The literature regarding the relative susceptibility to atherosclerosis of the aortic arch and pulmonary artery of rabbits is inconsistent. Atherosclerosis in the pulmonary artery has been variously reported to be similar or more extensive than that in the aortic arch,2 5 an arterial region equidistant from the heart, or to be reduced compared with that in the entire aorta.4 7 8 9 These are mutually conflicting observations because atherosclerosis is greater in the aortic arch than in the entire aorta.5 11 12 13 14 15 In a companion article in this issue of Circulation Research,16 we provide evidence suggesting that the apparently conflicting data for relative susceptibility to atherosclerosis for aortic arch and pulmonary artery might be explained by differences in the time course of development of atherosclerosis in these arterial regions. Such differences could be explained by shifts in the processes delivering cholesterol to, and removing cholesterol from, these arterial regions during the development of atherosclerosis that differ between the pulmonary artery and the aortic arch.
The mechanism(s) that promotes atherosclerosis in the pulmonary artery is not clear. Most of the cholesterol in atherosclerotic aortas is derived from plasma lipoproteins,17 18 19 20 and the pulmonary artery is relatively permeable to plasma proteins21 and LDL.22 23 24 25 26 However, rates of lipoprotein degradation, a process that delivers cholesterol to arterial cells, have not been assessed for the pulmonary artery. Increased arterial concentrations of undegraded LDL may increase susceptibility to atherosclerosis.27 28 Previous data indicate that the pulmonary artery has a higher distribution volume for albumin than does the aorta,29 but data for concentrations of undegraded LDL in the pulmonary artery are lacking. The goal of the present study was to investigate permeability to LDL, rates of LDL degradation, and concentrations of undegraded LDL for the intima-media of the pulmonary artery compared with the aortic arch and the descending thoracic aorta, an arterial region less susceptible to atherosclerosis than the aortic arch.5 11 12 13 14 15 Because atherosclerosis develops to a significant degree only in hypercholesterolemic individuals, we compared normal rabbits with those made hypercholesterolemic by feeding cholesterol for a short time. For normal rabbits, permeability to LDL, rates of LDL degradation, and concentrations of undegraded LDL for the intima-media of the pulmonary artery were similar to the corresponding values for the aortic arch and greater than those for the descending thoracic aorta when expressed on a weight basis. These differences in LDL transport and metabolism and the changes in these parameters after feeding cholesterol for 8 days roughly parallel the relative susceptibility to atherosclerosis in these arterial regions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rabbits
These studies used sexually mature young female New Zealand White rabbits from Robinson Services, Inc (Winston-Salem, NC). All rabbits were acclimated to the animal facility for
1 week before
entering the various studies, during which time they were fed
cholesterol-free rabbit chow (Prolab, Agway). Rabbits
weighed 2.5 kg before entering the various studies and 2.57±0.03 kg
(mean±SEM, n=39) at the end of the studies. Normal (control) rabbits
were studied while consuming cholesterol-free rabbit chow;
cholesterol-fed rabbits were studied after they had
consumed the same diet supplemented with 2.5% corn oil and 0.5%
cholesterol (Table 1
). All
rabbits were fed 100 g of their respective diets each day. Blood
samples (1 mL) were collected after an overnight fast while the rabbits
were consuming cholesterol-free rabbit chow and also after
they were fed cholesterol for 4 or 5 days.30
All blood samples were collected into 0.01 vol of 0.4 mol/L
EDTA.30
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Isolation of LDL for Reinjection Studies
LDL (1.020<d<1.060 g/mL) for labeling was isolated at
4°C by centrifugation in an SW41 rotor (Beckman
Instruments Inc) at 288 000g for 13.5 hours through a KBr
density gradient (modified from Reference 3131 ) formed by layering 3.75
mL of 1.060 g/mL and 3.9 mL of 1.00 g/mL density
solutions over 4.35 mL of the d<1.080 fraction32 isolated
from fresh plasma.26 Female New Zealand White rabbits fed
cholesterol-free rabbit chow were used as plasma donors.
These rabbits were exsanguinated after anesthetizing with
ketamine hydrochloride (100 mg/kg) and immobilizing with
xylazine (12 mg/kg). To limit degradation of apo B by
proteolysis and oxidation, blood was collected into 1 mg/mL
disodium EDTA, 1 µmol/L
D-phenylalanyl-L-prolyl-arginine
chloromethyl ketone, and 25 kallikrein inhibitory units/mL
aprotinin; 0.5 mmol/L phenylmethylsulfonyl fluoride
was added to plasma obtained after
centrifugation.26 LDL was washed by
recentrifugation through the same density gradient.
Isolated LDLs were dialyzed for 72 hours against six changes of 2000
vol of a buffer containing 0.15 mol/L NaCl, 20
mmol/L sodium phosphate, and 2 mmol/L disodium EDTA,
pH 7.4 (buffer A)28 33 in the dark. After dialysis,
protein content was determined.34
Labeling and Characterization of LDL
Eight experiments were performed, each with LDL isolated from a
different pool of plasma. For six experiments, LDL (13.9 to 25.5 mg
protein) was directly labeled with 131I (0.71 to 1.36
mCi/mg protein)35 36 and then covalently coupled to
125I-TC (4.7 to 7.4 nmol TC and 0.71 to 1.36 mCi per mg
protein) with cyanuric chloride.35 37 For two experiments,
LDL (10.8 to 11.2 mg protein) was coupled to 125I-TC only
(7.1 to 7.4 nmol TC and 0.89 to 0.92 mCi/mg protein).35 37
Labeled LDLs were dialyzed for 22 to 43 hours with five to seven
changes of 1000 to 2000 vol of buffer A.28 33 Labeled LDLs
were sterilized by filtration27 before injection 5 or 6
days after isolation of LDL.
Specific activities were 128±26 (n=6) cpm/ng for 131I and 981±186 (n=8) cpm/ng for 125I-TC. Polyacrylamide gel electrophoresis25 38 39 of delipidated40 LDL showed only 2.6±0.3% (n=8) and 2.5±0.3% (n=6) of 125I-TC and 131I labels to be associated with apo E, similar to other studies with LDL isolated from normal rabbits.27 28 33 Agarose gel electrophoresis41 showed 94.8±0.9% (n=5) and 96.8±1.0% (n=3) of 125I-TC and 131I, respectively, to comigrate with unlabeled LDL. Radioactivity soluble in 10% trichloracetic acid25 39 accounted for 2.0±0.3% (n=8) and 2.3±0.4% (n=6) of 125I-TC and 131I labels, respectively, whereas 7.0±0.7% (n=8) and 4.4±1.1% (n=6) of these labels could be extracted with chloroform/methanol.40 Iodination, use, and disposal of labeled lipoproteins were performed by procedures recommended by the Bowman Gray School of Medicine Office of Health Protection.
Animal Studies
Intima-media permeability to LDL was studied in 8 normal
rabbits and 7 rabbits fed cholesterol (Table 1
). Rabbits
were injected intravenously with 125I-TC-LDL
(3.38±0.71x108 cpm/kg, n=15). To follow the decline of
plasma radioactivity, four 1-mL blood samples were collected at
increasing intervals after injection.33 Rabbits were
euthanized as described below 0.90±0.11 hours (normal rabbits, n=8) or
0.87±0.09 hour (rabbits fed cholesterol, n=7) after they
were injected with labeled LDL. We26 and
others42 have shown that intima-media permeability to LDL
is linear during the first hour after injecting LDL labeled with
iodinated TC.
Intima-media LDL degradation rates and concentrations of undegraded LDL
were studied in 11 normal rabbits and 13 rabbits fed
cholesterol (Table 1). Rabbits were injected
intravenously with 125I-TC,131I-LDL
(5.38±0.29x108 cpm 125I/kg and
1.06±0.11x108 cpm 131I/kg, respectively;
n=24). Blood samples were collected at 5 and 15 minutes and at
increasing intervals after injection until rabbits were euthanized at
35.6±3.7 hours (normal rabbits, n=11) or 54.6±7.1 hours (rabbits fed
cholesterol, n=13) after injection.27 28
At the end of the study, a 10-mL blood sample was collected, and then the rabbits were anticoagulated with 1000 IU heparin.27 One minute later, the rabbits were euthanized with pentobarbital sodium (100 mg/kg body wt) and immediately perfused with 1 L of 0.15 mol/L sodium phosphate buffer, pH 7.3.33 The arterial system was fixed in situ by perfusing with half-strength Karnovsky's fixative for 10 minutes.33 All procedures with animals were approved by the Bowman Gray School of Medicine of Wake Forest University Animal Care and Use Committee.
Arterial Sampling
After fixation in situ, the aorta and pulmonary artery
trunk were removed along with the heart.26 Fixation was
continued overnight in half-strength Karnovsky's
fixative.27 28 Fixation in this way preserves the TC label
present on undegraded LDL and products of aortic LDL
degradation.35 The aorta and pulmonary artery were
separated from the heart at the aortic and pulmonary valves,
respectively. The thoracic and abdominal aorta were
separated.30 After adventitial tissue was removed from the
thoracic aorta and pulmonary artery, these arterial
segments were opened longitudinally, pinned flat, and photographed. The
aortic arch was separated from the descending thoracic
aorta,30 and the arterial samples were
photographed again. Fixed arterial samples were weighed and
counted for radioactivity. Surface areas of arterial
samples were determined by planimetry.27 28 33
Plasma and Lipoprotein Cholesterol Concentrations
Blood samples collected just before the animals were euthanized
were immediately mixed with disodium EDTA to a final concentration of
2.7 mmol/L. VLDL+IDL, LDL, and HDL were isolated from
plasma by differential ultracentrifugation at d<1.020,
1.020<d<1.060, and d>1.060 g/mL, respectively.32
Plasma lipoproteins were also separated by
electrophoresis.28 33 41 Cholesterol
concentrations in plasma were determined43 in the CDC
Standardized Lipid Analytical Laboratory of the Bowman Gray School of
Medicine. LDL cholesterol concentrations were determined as
described previously.28
Radioassay
Total and trichloroacetic acid–soluble 125I and
131I radioactivity in plasma, lipoprotein fractions, and
arterial samples was determined in a well-type gamma
counter with a 3-in crystal (Cobra II autogamma, Packard).
Radioactivity in all samples was corrected for background
radioactivity, for overlap of energy spectra of 125I and
131I when both were present, and for isotopic
decay.
LDL Transport Into the Intima-Media
Intima-media permeability to LDL was determined by dividing
intima-media radioactivity by the area under the decline of
protein-bound radioactivity in plasma from injection of labeled LDL
until the death of the animal.33 This provides a measure
of the intima-media permeability to LDL that is independent of the
plasma LDL concentration. Mass transport of LDL cholesterol
into the intima-media was determined by multiplying intima-media
permeability for individual rabbits by the LDL cholesterol
concentration of each rabbit.33
Intima-Media LDL Degradation Rate
The total body FCR of LDL was determined by fitting a
biexponential equation to data for the decline of protein-bound
radioactivity in plasma.27 28 The fraction of the injected
dose of labeled LDL degraded and total body degradation of LDL during
the experiments were calculated.27 28 125I-TC
radioactivity representing products of intima-media LDL
degradation was determined from protein-bound intima-media
125I-TC and 131I radioactivity and the ratio of
protein-bound 125I/131I radioactivity in
plasma.27 28 Intima-media LDL degradation rates were
calculated as fractions of the plasma LDL pool using data for
intima-media 125I-TC degradation products, the total
body FCR, and total body LDL degradation during the
experiments.27 28 Intima-media LDL degradation was
calculated as the amount of LDL cholesterol by multiplying
rates expressed as fractions of the plasma LDL pool by LDL
cholesterol concentrations of individual
rabbits.27 28
Intima-Media Concentration of Undegraded LDL
Intima-media concentrations of undegraded LDL were calculated as
percentages of the plasma LDL concentration by dividing protein-bound
intima-media 131I radioactivity representing
undegraded LDL by the final plasma concentration of protein-bound
131I.27 28 Intima-media concentrations of
undegraded LDL were also calculated as concentrations of LDL
cholesterol by multiplying concentrations as percentages of
the plasma LDL concentration by the LDL cholesterol
concentrations of individual rabbits.27 28
Statistical Methods
ANOVA with a multiple-measures design44 was used to
investigate differences among the three arterial regions
for control and cholesterol-fed rabbits. When the ANOVA was
significant, pairwise comparisons were performed between
arterial regions by paired t
tests.11 Corresponding data for normal rabbits and those
fed cholesterol were compared by independent-sample
t tests or Wilcoxon's two-sample rank
test.45 Probability values were adjusted using the
Bonferroni criteria to account for multiple comparisons.46
ANOVA with a multiple-measure design and grouping by
diet44 was used to investigate overall effects of
cholesterol feeding on the arterial regions.
When variances were proportional to mean values, data were transformed
to logarithms before statistical analysis.45 A
value of P<.05 was considered significant.
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Results |
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Plasma Cholesterol Concentrations
Plasma cholesterol concentrations did not differ between control rabbits used in the studies of intima-media permeability and those used for intima-media LDL degradation and concentration or between cholesterol-fed rabbits used for each of those studies (Table 1
). Plasma and LDL cholesterol
concentrations of cholesterol-fed rabbits were 17-fold and
16-fold the values for control rabbits, respectively.
Labeled LDL
In these studies, the ratio of the plasma LDL FCR calculated from
protein-bound 131I and 125I was 1.02±0.02
(n=24), in agreement with our earlier results.28 This
suggests that the concentration of EDTA used here and in the previous
studies28 is sufficient to prevent the oxidation and
subsequent rapid plasma clearance of LDL labeled with 131I
that was observed when LDL was dialyzed with much lower concentrations
of EDTA.47 At the end of the studies of intima-media
permeability, only 1.1±0.2% (n=15) of the protein-bound label
remaining in plasma could be isolated in the d<1.020 g/mL
fraction, whereas only 3.0±0.3% (n=15) of this label showed 
mobility on agarose electrophoresis. Corresponding values at the end of
the studies of intima-media LDL degradation and concentration of
undegraded LDL were 1.6±.2% (n=24) and 2.5±0.2% (n=24) of
125I-TC and 131I labels, respectively, and
5.7±1.3% (n=12) and 4.0±1.2% (n=12) of 125I-TC and
131I labels, respectively. Thus, nearly all of the
intima-media radioactivity would have entered the intima-media on LDL,
a necessary condition for the calculation of intima-media permeability,
LDL degradation rate, and concentration of undegraded LDL.
LDL Transport into the Intima-Media
We first considered whether differences in intima-media
permeability to LDL among the pulmonary artery, aortic arch,
and descending thoracic aorta might explain relative susceptibility to
atherosclerosis for these arterial regions.
Intima-media permeability to LDL differed among arterial
regions for both normal and cholesterol-fed rabbits when
expressed per unit arterial weight and when expressed per
unit arterial surface area (Table 2). However,
hypercholesterolemia did not influence
intima-media permeability of any arterial region. Expressed
per unit arterial fixed weight, intima-media permeability
was similar for the pulmonary artery and aortic arch and 2-
to 3-fold that for the descending thoracic aorta. Expressed per unit
arterial surface area, intima-media permeability to LDL was
greater for the aortic arch than pulmonary artery and greater
for these arterial regions than for the descending thoracic
aorta.
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Fig 1 shows the amount of LDL
cholesterol transported into the intima-media of the
pulmonary artery, aortic arch, and descending thoracic aorta
given intima-media permeabilities shown in Table 2. Mass transport of
LDL cholesterol into all arterial regions was
greatly increased in cholesterol-fed rabbits as a result of
hypercholesterolemia. For normal rabbits, LDL
transport into the pulmonary artery and aortic arch were
similar per unit arterial fixed weight and greater than
that into the descending thoracic aorta. A similar pattern was evident
for rabbits fed cholesterol, except that the difference
between the pulmonary artery and the descending thoracic aorta
was not significant. Per unit surface area, LDL transport into the
intima-media was somewhat but not significantly greater in the aortic
arch than in the pulmonary artery and greater in these
arterial regions than in the descending thoracic aorta.
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Intima-Media LDL Degradation Rate
Because intima-media degradation of LDL increases the cellular
cholesterol burden and might thus promote
atherosclerosis, we next considered regional variation
in the intima-media LDL degradation rate. Rates of intima-media LDL
degradation were first investigated as a fraction of the plasma LDL
pool (Table 3). There were regional
differences in intima-media fractional rates of LDL degradation for
normal and cholesterol-fed rabbits and for fractional rates
of LDL degradation expressed both per unit arterial weight
and per unit arterial surface area. For both normal and
cholesterol-fed rabbits, fractional rates of LDL
degradation per unit arterial weight were similar for
pulmonary artery and aortic arch and 45% to 77% greater for
these arterial regions than for the descending thoracic
aorta. In comparison, when expressed per unit arterial
surface area, the intima-media LDL degradation rate was 32% to 64%
higher for the aortic arch than for the pulmonary artery and
172% to 188% higher for the aortic arch than for the descending
thoracic aorta. Whether expressed per unit weight or per unit surface
area, the fractional rate of intima-media LDL degradation was reduced
by cholesterol feeding, with greater reductions for the two
aortic regions than for the pulmonary artery.
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Fig 2 shows the amount of LDL
cholesterol degraded per day by the intima-media of the
pulmonary artery, aortic arch, and descending thoracic aorta
given the fractional rates shown in Table 3. In contrast to rates of
LDL degradation as a fraction of the plasma LDL pool, rates of
intima-media LDL cholesterol degradation were greatly
increased in cholesterol-fed rabbits as a result of
hypercholesterolemia. For both normal and
cholesterol-fed rabbits, rates of LDL
cholesterol degradation per unit weight were similar for
the aortic arch and pulmonary artery and higher in both of
these arterial regions than in the descending thoracic
aorta. In comparison, per unit surface area, the intima-media LDL
degradation rate for both normal and cholesterol-fed
rabbits was greater for the aortic arch than for the pulmonary
artery and the descending thoracic aorta, with no difference between
the latter two arterial regions.
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Intima-Media Concentration of Undegraded LDL
Because the accumulation of undegraded LDL in the intima-media
could promote atherosclerosis, we next considered the
variation in intima-media concentration of undegraded LDL among the
arterial regions. Intima-media undegraded LDL was first
determined as a percentage of the plasma LDL concentration (Table 4). There were regional differences in
intima-media concentrations of undegraded LDL for both normal and
cholesterol-fed rabbits. For normal rabbits, intima-media
concentrations of undegraded LDL were similar for the pulmonary
artery and aortic arch and almost twice as great for these
arterial regions as for the descending thoracic aorta.
Similar trends were observed for rabbits fed cholesterol,
but the only significant difference was that between the aortic arch
and the descending thoracic aorta. Cholesterol feeding
reduced intima-media concentrations of undegraded LDL when these
concentrations were expressed as a percentage of the plasma
concentration, with the greatest reduction in the pulmonary
artery.
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However, these lower intima-media concentrations of undegraded LDL as a
percentage of the plasma in the rabbits fed cholesterol
(Table 4) corresponded to much larger amounts of LDL
cholesterol (Fig 3). For
normal rabbits, intima-media concentrations of undegraded LDL as LDL
cholesterol were similar for the pulmonary artery
and aortic arch and greater for these arterial regions than
for the descending thoracic aorta. A similar trend was observed for
rabbits fed cholesterol, but the only significant
difference was that between the aortic arch and the descending thoracic
aorta.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The aim of these studies was to investigate intima-media LDL transport and metabolism for the pulmonary artery, aortic arch, and descending thoracic aorta and to consider whether differences in intima-media LDL transport and metabolism might explain the relative susceptibility to atherosclerosis of these arterial regions. The principal findings of these studies were as follows: First, cholesterol feeding influenced intima-media rates of LDL degradation and concentrations of undegraded LDL but had no affect on intima-media permeability to LDL. Second, for both normal and cholesterol-fed rabbits, intima-media permeability to LDL, LDL degradation rates, and concentrations of undegraded LDL were similar for the pulmonary artery and aortic arch and greater than for the descending thoracic aorta when expressed on a weight basis, roughly parallel to the relative susceptibility to atherosclerosis. In contrast, when intima-media permeability to LDL and rates of LDL degradation were expressed per unit arterial surface area, values for the pulmonary artery were intermediate between those for the aortic arch and descending thoracic aorta. These differences reflect the lower weight per unit area for the pulmonary artery compared with the aortic arch.
Intima-Media LDL Transport and Metabolism for
Pulmonary Artery and Aortic Arch
The similarity between pulmonary artery and aortic arch
for all aspects of intima-media LDL transport and
metabolism was somewhat surprising because these
arterial regions differ in structure, cellularity,
thickness, and blood pressure29 48 and possibly in other
ways. However, our data for high intima-media permeability to LDL for
the pulmonary artery are consistent with earlier
work.22 23 24 25 26 As far as we know, no previous study has
compared intima-media rates of LDL degradation between the
pulmonary artery and aortic arch or any aortic region. However,
an earlier study in rabbits investigated LDL degradation in vivo in
corresponding arteries and veins (eg, thoracic aorta and thoracic vena
cava).49 That study reported similar LDL degradation rates
for corresponding arteries and veins on a weight basis but 50% to
170% higher rates for arteries than for the corresponding veins when
LDL degradation rates were expressed per unit surface
area.49 This is consistent with our findings for
the pulmonary artery and aortic arch. Another study reported
that the tissue space for albumin was greater in the
pulmonary artery than in the systemic arteries, including the
aorta,29 but no other study has investigated
concentrations of undegraded LDL in the pulmonary artery.
However, one in vitro study reported similar concentrations of
undegraded LDL for the femoral artery and saphenous
vein,50 whereas another study demonstrated the presence of
apo B in both the aorta and pulmonary
artery.51
Changes in Intima-Media LDL Transport and Metabolism
After Cholesterol Feeding
In these studies, as in another,28 we observed
intima-media rates of LDL degradation for the aortic arch and
descending thoracic aorta to be decreased in fractional terms but
increased as amounts of LDL cholesterol in rabbits fed
cholesterol for 9.4 days (Table 3, Fig 2). In the earlier
study,28 intima-media concentrations of undegraded LDL in
rabbits fed cholesterol for 8 days were reduced as
percentages of the plasma in the aortic arch but were unchanged in the
descending thoracic aorta. In contrast, in this study with more than
twice as many animals at each time point, we found
hypercholesterolemia of similar degree and
duration to reduce the intima-media concentrations of undegraded LDL to
similar degrees in the aortic arch and descending thoracic aorta (45%
and 46%, respectively; Table 4). These studies extend the earlier
observations to include the pulmonary artery where we observed
hypercholesterolemia to influence intima-media
rates of LDL degradation and concentrations of undegraded LDL in a
manner similar to that in the aortic arch. However, subtle differences
between these two arterial sites were present as
discussed below.
Intima-Media LDL Transport and Metabolism on a Surface
Area and Weight Basis
Interpretation of intima-media LDL transport and
metabolism on a surface area and a weight basis are to some
degree dependent on the "fate" of LDL within the artery, as
discussed below. Because LDL enters the intima-media via transport
through the endothelium and the abluminal
surface,52 one could argue that permeability is more
properly expressed per unit intima-media surface area than per unit
intima-media weight. Combining data from the present study with
that of a companion study,16 we estimate that during the
first 16 days of cholesterol feeding at least 83%, 94%,
and 96% of the LDL cholesterol entering the
pulmonary artery, aortic arch, and descending thoracic aorta,
respectively, were removed and did not contribute to
arterial cholesterol accumulation,
consistent with previous studies.25 33 53 In
addition, other work suggests that removal of lipoprotein from the
artery may be impaired by increased thickness of the
intima-media.33 54 Thus, the measurement of intima-media
permeability per unit weight, which takes intima-media thickness into
account, might be more relevant to atherogenesis than measurements
based only on intima-media surface area. A similar argument would hold
for comparison of intima-media LDL degradation on the basis of surface
area or weight. If LDL degradation were to occur only in the intima but
not in the media, then it would be more proper to determine
intima-media LDL degradation rate per unit surface area than per unit
weight. However, more degradation of LDL occurs in the inner media of
the rabbit aorta than in the intima.27 35 There is no
quantitative information on regional variation in relative proportion
of the media that actively degrades LDL. However, a thicker media may
impair removal of cholesterol (contributed by LDL
degradation) from intimal cells by reverse cholesterol
transport, since experiments in pigs showed that most HDL effluxing
from the aorta does so via the abluminal surface.55
Model: Role of Intima-Media LDL Transport and
Metabolism in Atherosclerosis
In earlier studies in rabbits, we found that aortic arch and
branch sites of descending thoracic and abdominal aortas, aortic sites
that are most susceptible to atherosclerosis in this
species,56 57 58 59 60 61 62 degraded greater amounts of LDL and
contained higher concentrations of undegraded LDL than did adjacent
less susceptible sites, and that such differences were exaggerated
during the first 16 days of cholesterol
feeding.27 28 In contrast, consistent with results
of the present studies, arterial permeability to LDL
was not altered during the first 16 days of cholesterol
feeding33 or even after 10 months of
hypercholesterolemia for arterial
regions free of atherosclerosis.25 This
suggests that hypercholesterolemia initiates
atherogenesis by a process(es) other than increased
arterial permeability to LDL. Increased rates of LDL
degradation directly increase delivery of cholesterol to
arterial cells and promote cholesterol
accumulation unless cholesterol removal also increases by
reverse transport processes. Higher intima-media concentrations of
undegraded LDL may also increase atherosclerosis by a
number of mechanisms: by resulting in concentrations of oxidatively
modified LDL that reach critical threshold values that promote the
entry of monocytes (either directly63 or secondary to
endothelial expression of adhesion
molecules64 65 and chemotactic factors66 ), by
inhibiting the mobility of tissue macrophages,63
and by promoting the uptake by macrophages of LDL modified by
oxidation.67 High intima-media concentrations of
undegraded LDL may also increase atherogenesis by enhancing the
formation of complexes of LDL with arterial proteoglycans,
increasing the macrophage uptake of LDL in the complexes and
promoting oxidation of LDL in the complexes, which further increases
the macrophage uptake of LDL.68 It seems likely
that some interval of exposure to
hypercholesterolemia would be needed to
initiate this cascade of events.
If the model described above is correct, then one might expect increased rates of intima-media degradation to contribute to the intima-media cholesterol accumulation that occurs very early after the onset of cholesterol feeding30 and to the later stages of atherosclerotic lesion development. In comparison, consequences of increased arterial accumulation and retention of undegraded LDL27 28 33 might be delayed several weeks and contribute relatively more to later stages of atherogenesis. As described above, intima-media rates of LDL degradation and concentrations of undegraded LDL were greater for the aortic arch than for the descending thoracic aorta and changed in parallel in rabbits fed cholesterol for 9.4 days. Based on those metabolic parameters, the model presented above would predict both cholesterol accumulation in the intima-media after short intervals of cholesterol feeding and the development of atherosclerotic lesions to be greater for the aortic arch than for the descending thoracic aorta, exactly what has been observed in previous studies.5 11 12 13 14 15 30 In an earlier study, rates of LDL cholesterol degradation by the aortic arch and descending thoracic aorta changed very little between 8 and 16 days of cholesterol feeding.28 This would predict linear accumulation of cholesterol in these aortic regions during the first 16 days of cholesterol feeding, as was observed in the companion article.16 However, this model alone would not explain the relatively higher proportion of esterified cholesterol in the pulmonary artery than in the aortic arch that was observed both early16 and late2 16 in atherogenesis. To explain such differences, one would need to postulate differences in cellular composition or metabolism between these arterial regions as discussed in the companion article.16
In normal rabbits, intima-media rates of LDL degradation and
concentrations of undegraded LDL were similar (on a weight basis) for
the aortic arch and pulmonary artery. However, feeding
cholesterol for 9.4 days increased the rate of LDL
cholesterol degradation relatively more in the
pulmonary artery than in the aortic arch (Fig 2). In contrast,
feeding cholesterol for 9.4 days increased the intima-media
concentration of undegraded LDL as LDL cholesterol
relatively less for the pulmonary artery than for the aortic
arch (Fig 3). If such subtle differences in the regulation of
intima-media LDL degradation rates and concentrations of undegraded LDL
continue after longer periods of cholesterol feeding, such
differences would predict the following: First, early in atherogenesis,
cholesterol would accumulate more rapidly in the
pulmonary artery than in the aortic arch, as was observed in
the companion article.16 Second, at a later point in
atherogenesis when the sequelae of the intima-media concentrations of
undegraded LDL described above become predominant, atherogenesis would
proceed at a slower rate in the pulmonary artery than in the
aortic arch. If this is indeed the case, then relative degrees of
atherosclerosis in the pulmonary artery and the
aortic arch would differ after different degrees and duration of
hypercholesterolemia, as appears to be the
case.2 4 5 6 7 8 9
In summary, we found arterial transport and metabolism of LDL to be similar for the aorta arch and pulmonary artery and to be increased in these two arterial regions compared with the descending thoracic aorta. Feeding cholesterol for 8 to 9.4 days did not influence intima-media permeability to LDL but regulated intima-media rates of LDL degradation and concentrations of undegraded LDL, with parallel changes in the aortic sites but subtle differences between the pulmonary artery and the aortic arch. The relative differences in arterial transport and metabolism among these arterial regions in normal rabbits and the changes after 8 to 9.4 days of cholesterol feeding correlate with the variation in susceptibility to atherosclerosis among these arterial regions. These results underscore the importance of arterial transport and metabolism in determining susceptibility to atherosclerosis and provide a mechanism by which the relative susceptibility to atherosclerosis in these arterial regions might be explained.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grant HL-45027. Dr Schwenke is an Established Investigator of the American Heart Association. The author gratefully acknowledges the skillful technical assistance of Christina Tulbert, Elizabeth Ann Jordan, and John Mason.
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Footnotes |
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Reprint requests to Dawn C. Schwenke, PhD, Department of Pathology, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1072.
Received February 14, 1997; accepted June 1, 1997.
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References |
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