© 1997 American Heart Association, Inc.
Articles |
Long-term Probucol Treatment Reverses the Severity of Myocardial Injury in Watanabe Heritable Hyperlipidemic Rabbits
From the First Department of Medicine (S.H., N.Y., J.I., K.A., T.K., M.H.) and Department of Pathophysiology (K.A., T.K.), Osaka University Medical School, Osaka, Japan.
Correspondence to Shiro Hoshida, MD, PhD, Cardiovascular Division, Osaka Rosai Hospital, 479-3 Nagasone-cho, Sakai, Osaka 591, Japan.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract We previously reported that administration of NO donors ameliorates the severity of myocardial injury in cholesterol-fed rabbits. We now evaluated the effects of probucol, a lipid-lowering antioxidant that can preserve endothelium-dependent relaxation (EDR), in the aortas of cholesterol-fed rabbits. We examined the effects of short-term (7 days) or long-term (24 weeks) administration of 1% probucol on the size of infarcts resulting from 30 minutes of coronary occlusion followed by reperfusion (for 48 hours) in Watanabe heritable hyperlipidemic (WHHL) rabbits. Infarcts in untreated WHHL rabbits were significantly larger than those in the rabbits receiving the long-term but not the short-term treatment with probucol (72.2±5.4%, 37.6±6.4%, and 66.7±3.5%, respectively). Long-term probucol treatment also significantly reduced myeloperoxidase activity in both ischemic and nonischemic myocardium and suppressed P-selectin expression in the coronary vasculature. No significant differences were observed in hemodynamic parameters during myocardial ischemia/reperfusion. Long-term probucol treatment significantly reduced the surface area of atherosclerotic plaque lesions in the aorta (24.4±3.8% vs 46.3±6.3, P<.05). Moreover, long-term probucol treatment restored acetylcholine-induced EDR in aortic rings but did not affect sodium nitroprusside–induced relaxation. Finally, long-term probucol treatment resulted in significantly elevated cGMP levels in the aorta. These results indicate that long-term probucol treatment significantly ameliorates myocardial injury in heritable atherosclerotic rabbits, perhaps by reducing the accumulation of leukocytes in the myocardium and atherosclerotic vascular lesions. Thus, long-term administration appears to suppress the progression of atherosclerotic vascular disease in this animal model.
Key Words: infarct limitation • atherosclerosis • endothelium-dependent relaxation • P-selectin • probucol
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Pharmacological intervention to inhibit the progression of myocardial necrosis is clinically important because infarct size is an independent determinant of the prognosis of patients with acute MI. However, agents that limit infarct size in animal models of myocardial ischemia and reperfusion do not necessarily exert a similar favorable effect in humans. A reason for this discrepancy is the occurrence of atherosclerotic vascular lesions in humans but not in some animals. The extent of myocardial injury produced by coronary occlusion followed by reperfusion is exacerbated in hypercholesterolemic animals.1 2 3 We recently reported that the severity of injuries induced by myocardial ischemia and reperfusion is increased in atherosclerotic rabbits but can be effectively reversed by treatment with an NO donor.4 In contrast, NO donors do not limit infarct size in normal rabbits.4
EDR is impaired in atherosclerotic animals and humans,5 6 7 8 perhaps because of the overproduction of free radicals in the diseased vascular tissue.9 10 11 This hypothesis is supported by findings that antioxidative agents reduce the extent of atherosclerotic lesions in the aortas of atherosclerotic animals12 13 and inhibit the progression of coronary artery atherosclerosis in humans.14 Probucol is a lipid-soluble, potent antioxidant15 16 that can slow the progression of atherosclerosis in heritable hypercholesterolemic rabbits.17 18 The present study examined the effects of short-term or long-term probucol treatment on infarct size and its relationship to leukocyte accumulation in the myocardial ischemic region and to the suppression of atherosclerotic lesions in WHHL rabbits. Since expression of P-selectin, one of the adhesion molecules related to the interaction between leukocytes and the endothelium that has been shown to be induced by lysophosphatidylcholine,19 an atherogenic lysophospholipid contained in oxidized LDL, myocardial expression of P-selectin assessed by immunohistochemistry was also compared between untreated and probucol-treated rabbits.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Nine male WHHL rabbits (2 months old) were fed a diet of standard laboratory food for 24 weeks. Seven male WHHL rabbits (2 months old) received standard laboratory food with 1% probucol for 24 weeks (long-term treatment). Another 7 male WHHL rabbits (2 months old) were fed standard laboratory food for 24 weeks with probucol treatment during the last 7 days only (short-term treatment). In addition, eight male Japanese white rabbits received standard laboratory food as normal controls. Water was available ad libitum. All animals (Kitayama Labs, Kyoto, Japan) were housed under identical conditions (Nihon Bioresearch Center, Inc). This study was conducted in accordance with the Guide for the Care and Use of Experimental Animals.
Blood Samples
Samples of arterial blood from WHHL rabbits were
collected immediately before the 24-week experiment period began and
again at the end of 24 weeks to determine the plasma concentrations of
TC, TG, HDL-C, and antioxidant levels. Plasma TC20 and
TG21 were quantified using enzymatic methods. In treated
rabbits, plasma probucol levels were determined by
high-performance liquid chromatography as
described by Mao et al.22 The plasma concentration of
-tocopherol was determined by the method of Stocker et
al.23
Experimental Protocol
After receiving the assigned diet for 24 weeks, the WHHL rabbits
were anesthetized by injection of 30 mg/kg body weight
sodium pentobarbital into the marginal ear vein, intubated orally, and
ventilated with a small-animal respirator (model 683, Harvard
Apparatus). MIs were induced as described
previously.4 24 Myocardial ischemia was confirmed
by cyanosis and akinesis in the ischemic region near the
occluded branch of the left circumflex coronary artery.
Arterial blood pressure and heart rate were monitored
continuously throughout the 30-minute ischemia and 60-minute
reperfusion periods. The surgical wounds were repaired 60 minutes after
reperfusion, and the rabbits were returned to their cages for recovery.
Forty-eight hours after reperfusion, the rabbits were injected
intravenously with 1000 U heparin and administered an
overdose of pentobarbital. The hearts then were removed for postmortem
analysis. MIs were induced similarly in normal control rabbits.
Measurement of Infarct Size
The size of the myocardial infarct was assessed as described
previously.4 24 In brief, the hearts were perfused with
saline through the aorta to wash out residual blood. Evans blue dye was
introduced after the left coronary branch had been reoccluded
to estimate the area perfused by the occluded artery. The LV was then
cut into six pieces that were incubated with
triphenyltetrazolium chloride to stain
noninfarcted regions. The area at risk was defined as the ratio of
ischemic region mass to LV mass. The size of the infarct was
defined as the ratio of infarcted region mass to ischemic
region mass.
Assessment of Leukocyte Accumulation
MPO activity was assessed by the method of Bradley et
al,25 with the modifications described
previously.26 27 Myocardial tissue was obtained from
ischemic and nonischemic regions of the heart and
frozen rapidly in liquid N2. One unit of MPO activity was
defined as that amount of enzyme necessary to degrade 1 µmol of
peroxide per minute at 30°C.
Immunohistochemistry
Immunohistochemistry was performed as previously
reported.28 The LV was placed on cryostat chucks with OCT
embedding medium (Lab-Tek Products) on dry-iced acetone and stored
at -80°C. Cryostat sections (5 µm) were mounted on uncoated
glass slides and then air dried. The sections were fixed in 100%
acetone at 4°C for 10 minutes. The specimens were incubated with a
monoclonal mouse anti-human P-selectin antibody (WAPS 12.2,
Endogen Inc) for 60 minutes at room temperature. The cells were exposed
to peroxidase-conjugated, affinity-purified anti-mouse IgG (Kirkegaard
& Perry Laboratories Inc) for 30 minutes at room temperature. Specific
antigen-antibody complexes were visualized by development for 10
minutes in 0.02% 3-amino-9-ethylcarbazole (Aldrich-Chemie) and
0.03% H2O2 in acetate buffer (0.05
mol/L, pH 5.0). The sections were counterstained with
hematoxylin and then dehydrated. For the aforementioned
immunohistochemical procedures, controls were performed by replacing
the primary antibody with 10% nonimmune serum or PBS. Additional
controls were performed by omitting the secondary antibody. The
controls were always negative.
Assessment of Aortic Atherosclerosis
The surface area of atherosclerotic lesions in the thoracic
aorta was determined as described previously.4 In brief,
adventitial tissue was dissected from the aorta and the remaining blood
was rinsed away. Lesion surface area and total aortic surface area were
measured by planimetry of photographic images. To determine the TC
content of aortic tissue, the samples were homogenized with
20 volumes of chloroform/methanol (2:1, vol/vol). After
centrifugation the supernatants were dried under
N2, and the TC content was determined using enzymatic
methods.20 The myocardial cGMP content was measured by an
enzyme-linked immunosorbent assay (Amersham) after the tissue samples
had been homogenized in 0.1N HCl and the supernatants
obtained by centrifugation.
Assessment of EDR
The thoracic aorta was dissected and adhering perivascular
tissue removed. Arterial rings (5 mm long) were cut
and suspended from strain gauges to measure the isometric
circumferential force in an organ chamber (25 mL) filled with Tyrode's
solution containing 5.6 mmol/L glucose as described
previously.29 The solution was maintained at 37°C and
gassed with 95% O2–5% CO2. To determine
relaxation, the rings were precontracted by incubation with 1
µmol/L norepinephrine. Endothelial
control of vascular tone was assayed by addition of ACh (1
nmol/L to 10 µmol/L), whereas vasodilation of
smooth muscle cells was assessed by using SNP (1 nmol/L to
10 µmol/L).
Statistical Analysis
Results are expressed as mean±SEM. Differences in
hemodynamic changes over time were evaluated by
ANOVA. ANCOVA was used to compare the regression lines for the area
at risk and infarct tissue mass between treated and untreated rabbits.
A value of P<.05 was considered statistically
significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Mortality and Plasma Levels of Lipids and Antioxidants
One rabbit in the untreated group and one in the short-term treatment group died of ventricular fibrillation during coronary occlusion. Data from the 21 surviving WHHL rabbits were subjected to various analyses. Plasma concentrations of TC, TG, and HDL-C before the 24-week experimental period did not differ significantly between the untreated and probucol-treated rabbits (Table 1
). Probucol treatment did not
significantly affect the levels of TC and TG, although plasma HDL-C
concentrations were significantly reduced by treatment after 24 weeks
(Table 1). Plasma TC concentration was low in control rabbits (25±3
mg/dL; data not shown). Plasma -tocopherol levels
before and after the 24-week experimental period did not differ
significantly between untreated and the long-term treatment group of
WHHL rabbits. In both groups, however,
plasma -tocopherol levels were significantly lower at
the end of the experiment than at the beginning (P<.05;
Table 2). Plasma probucol levels in the treated WHHL rabbits were
similar to those found in other reports of treatment with 1%
probucol.17 18
|
|
Hemodynamic Variables
There were no significant differences in mean
arterial pressure in the four groups during
ischemia and reperfusion. The rate-pressure product, an
index of myocardial O2 consumption, also was similar in all
groups (Fig 1).
|
) and WHHL rabbits
without treatment (
) or treated with probucol for 7 days (
)
or 24 weeks (
). The rate-pressure product is defined as the
systolic blood pressure multiplied by heart rate.
Infarct Size
The infarct size (ie, the amount of necrotic tissue as a
percentage of the area at risk) was significantly higher in untreated
WHHL rabbits (72.2±5.4%) than in normal control rabbits (49.8±3.3%,
P<.05). Long-term probucol treatment significantly reduced
the infarct size in WHHL rabbits (37.6±6.4%, P<.05),
although the area at risk did not differ between the experimental
groups (Fig 2). However, short-term
treatment did not reduce infarct size (66.7±3.5%).
|
In all groups, the absolute infarct size was significantly correlated
(P<.05) with the size of the area at risk (control,
y=0.626x-0.208, r=.939; untreated
WHHL, y=0.887x-0.266, r=.837;
short-term treatment, y=0.713x-0.034,
r=.965; long-term treatment,
y=0.551x-0.255, r=.653). Regression
analysis demonstrated that this correlation differed
significantly between control and untreated WHHL rabbits and between
untreated WHHL rabbits and the long-term treatment group
(P<.05; Fig 3).
|
Leukocyte Accumulation
In all groups, MPO activity was significantly higher in
ischemic myocardium than in nonischemic
myocardium. MPO activity in ischemic
myocardium was significantly higher in untreated WHHL
rabbits than that in normal control rabbits and was effectively reduced
by long-term probucol treatment. Long-term probucol treatment
significantly reduced MPO activity, even in nonischemic
myocardium (Fig 4). However,
short-term probucol treatment did not reduce MPO activity in either
nonischemic or ischemic myocardium.
|
P<.05 vs untreated WHHL rabbits.
P-Selectin Expression
Expression of P-selectin was investigated in nonischemic
myocardium in the four experimental groups of rabbits. In
untreated WHHL rabbits (Fig 5A),
P-selectin localization appeared to be "granular" on the
coronary artery endothelium and
"nongranular" in the capillary endothelium.
P-Selectin is constitutively stored in the Weibel-Palade bodies of the
endothelium, and the interaction of anti–P-selectin
antibody and P-selectin appears to require endothelial
activation and translocation of active P-selectin to the cell
surface.30 In contrast, P-selectin expression was absent
or rare on the endothelium of the long-term treatment
group of rabbits (Fig 5B), which was similar to that in normal control
rabbits (data not shown). Although not shown, short-term probucol
treatment did not affect P-selectin expression in WHHL rabbits.
|
EDR
In aortic rings from normal control rabbits, ACh (1 nmol/L
to 10 µmol/L) induced relaxation in a
concentration-dependent manner, with a maximum relaxation observed at
10 µmol/L; at this ACh concentration, the
norepinephrine-induced precontraction was completely
reversed to basal levels (93±4%). In aortic rings from untreated WHHL
rabbits, ACh addition only led to a low degree of relaxation (19±12%
at 10 µmol/L; Fig 6).
Long-term probucol treatment, however, partially restored the
ACh-induced relaxation (47±7% at 10 µmol/L,
P<.05). Short-term probucol treatment did not affect the
ACh-induced relaxation. The vasodilatory response to the NO donor SNP,
in contrast, was similar in all four experimental groups. Aortic rings
from untreated and probucol-treated WHHL rabbits exhibited
dose-dependent vasodilation in response to increasing concentrations of
SNP (Fig 6), which did not differ significantly from the response in
normal rabbits.
|
Effect of Probucol on Aortic Atherosclerosis
Long-term administration of probucol effectively reduced the area
of atherosclerotic plaques in the thoracic aortas of WHHL rabbits, but
short-term treatment did not (Table 3).
The TC concentration of the aorta was significantly reduced by
long-term probucol treatment. The cGMP content of the aorta was also
significantly higher in the long-term treatment group than in untreated
WHHL rabbits (Table 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Antiatherosclerotic Effects of Probucol
It has been speculated that oxidative modification of LDL contributes to the atherogenic process.31 32 33 Probucol, which was originally developed as an antioxidant,15 inhibits the oxidative LDL modification by copper ions or endothelial cells.34 Several investigators have demonstrated probucol's antiatherosclerotic effects in animal models of atherosclerosis, including the WHHL rabbit.17 18 35 The present study confirms this observation.
Although probucol had previously been reported to lower cholesterol levels in WHHL rabbits,36 we did not detect any significant probucol-related decrease in plasma TC levels. This was not due to insufficient probucol levels, because the plasma probucol concentrations in this study were comparable to those measured in probucol-treated patients, whose LDL was resistant to cell-mediated and copper ion–mediated oxidation.34 Similarly, Carew et al18 reported that probucol may slow the progression of atherosclerosis by mechanisms unrelated to its cholesterol-lowering effect, eg, by inhibiting oxidative modification of LDL.
Preservation of EDR by Probucol
Some investigators have demonstrated impaired EDR in WHHL
rabbits.37 38 39 Considerable evidence indicates that excess
vascular oxidative stress contributes to an impaired EDR in
experimental atherosclerosis. For example, arteries
from cholesterol-fed rabbits have been shown to produce
excess superoxide anions,10 which readily
inactivate endothelium-derived relaxing
factor/NO.40 Accordingly, Keaney et al41
reported that an increase in vascular superoxide generation from the
aortas of cholesterol-fed rabbits was associated with
impaired EDR. Other studies have found that
endothelium-derived relaxing factor is also degraded
and that EDR is inhibited by oxidized LDL.42 43 The
present study is the first to report that probucol administration
partially restored EDR in WHHL rabbits. This effect did not result from
probucol-mediated changes in plasma TC levels or alterations in smooth
muscle sensitivity to SNP. On the other hand, we demonstrated that
aortic cGMP contents were significantly higher in the long-term
treatment group of rabbits than in untreated rabbits. These
observations suggest that long-term but not short-term probucol
treatment inhibits LDL oxidation, thus leading to suppression of NO
inactivation and restoration of EDR. Whether probucol directly
scavenges superoxide anions remains
controversial.41 44
Infarct-Limiting Effects of Probucol
We previously reported that inhibition of NO synthase exacerbates
myocardial injury produced by coronary
occlusion/reperfusion.24 The severity of myocardial injury
observed in long-term cholesterol–fed rabbits, which
exhibit reduced EDR,5 45 is ameliorated by administration
of an NO donor.4 However, EDR preservation alone does not
completely explain the effects of probucol on infarct size, because
long-term probucol treatment did not restore EDR to control levels,
whereas it reduced infarct sizes to those of control rabbits.
We investigated whether probucol-induced infarct limitation might be related to the drug's short-term antioxidative action per se. Several reports have shown that antioxidants can limit infarct size in a coronary occlusion/reperfusion model.46 47 We also reported that several antioxidants26 48 as well as a sulfhydryl compound27 significantly reduce infarct size in a canine model of MI. However, this mode of action of probucol is unlikely because short-term treatment with probucol did not reduce infarct size in WHHL rabbits.
The requirement for long-term probucol administration to yield its favorable effect suggests its influence on an interaction between chronic hypercholesterolemia and the mechanism mediating this effect. In this sense, the reduction of MPO activity in ischemic myocardium may be another possible mechanism underlying infarct size limitation by long-term probucol treatment. The extent to which leukocytes, especially polymorphonuclear leukocytes, accumulate in ischemic myocardium has been shown to be related to the progression of myocardial injury in a coronary occlusion/reperfusion model.48 49 The augmented expression of adhesion molecules involved in the interaction between leukocytes and coronary microvascular endothelium leads to enhanced leukocyte accumulation in the ischemic myocardium.30 50 One of these adhesion molecules, P-selectin, supports leukocyte rolling on the endothelial surface and was markedly expressed in the coronary endothelium of untreated WHHL rabbits, a result that was effectively suppressed by long-term but not short-term probucol treatment. If P-selectin expression induced by myocardial ischemia/reperfusion per se were important to augment leukocyte-endothelium interactions in the coronary bed and to an increase in infarct size, short-term probucol treatment would reduce infarct size in WHHL rabbits; however, short-term treatment did not reduce infarct size in the present study. Since P-selectin has also been shown to be induced by cytokines,51 oxygen radicals,52 and oxidized LDLs53 but suppressed by NO,54 long-term administration of probucol could reduce P-selectin expression in the coronary bed and ameliorate leukocyte adherence to the microvascular endothelium, resulting in a decreased accumulation of leukocytes in the ischemic myocardium and a reduction in infarct size. This hypothesis is consistent with our finding that long-term probucol treatment significantly reduced MPO activity not only in the ischemic but also in the nonischemic myocardium. Expression of other adhesion molecules in atherosclerotic vessels, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelium-leukocyte adhesion molecule-1,55 56 57 58 59 may also be involved in the enhanced leukocyte accumulation.
Study Limitations
WHHL rabbits suffer from severe coronary
atherosclerosis, which in its natural course leads to
myocardial lesions.36 60 61 While measuring infarct sizes,
we could not assess coronary artery atherosclerotic lesions in
our WHHL rabbits. It remains to be seen whether the beneficial effects
of probucol exist in the coronary arteries as well as in
conductance vessels because we did not examine the protective effect of
probucol on coronary EDR impairment. Therefore, we cannot rule
out the possibility that probucol-induced differences in
coronary atherosclerotic stenotic lesions may have
played a role in limiting infarct size. However, we observed no
macroscopic myocardial lesions in the nonischemic regions. The
favorable effects of long-term probucol treatment on coronary
atherosclerosis or the quality of the plasma
lipoproteins may not be the only possible explanation. Another factor
that determines the role and extent of MI is the native supply of
coronary collaterals, which is minimal in
rabbits.62 Although the coronary collateral supply
does not appear to be altered in animal models of
atherosclerosis, we cannot exclude the possibility that
long-term probucol treatment affected infarct size by modifying the
collateral circulation in WHHL rabbits. However, this seems unlikely,
as we did not observe any differences between the probucol-treated and
untreated animals in the area at risk.
Conclusions
The sizes of infarcts resulting from coronary occlusion
followed by reperfusion in heritable atherosclerotic rabbits were
increased versus those in normal rabbits but were significantly reduced
by long-term probucol treatment. Long-term probucol administration
reduced P-selectin expression, the accumulation of leukocytes in the
myocardial tissue, and the area of atherosclerotic plaque lesions in
the thoracic aorta and partially but significantly restored aortic EDR.
Clinical epidemiological data suggest that a high dietary intake of
lipid-soluble antioxidants, such as ß-carotene and vitamin E, reduces
the risk of atherosclerotic vascular disease.63 64 65
Probucol appears to be a promising antioxidative agent that can reduce
the incidence of MI and also inhibit the progression of myocardial
injury, thus helping to reduce the mortality rate due to this disease.
However, multicenter studies are required to clarify probucol's
efficacy in preventing MI and in improving the outcome in patients with
or without hyperlipidemia.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported in part by research grants from the Ministry of Education, Science, and Culture of Japan (to S.H.). We thank N. Kozuka for her excellent secretarial assistance.
Received August 26, 1996; accepted May 20, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Golino P, Maroko PR, Carew TE. The effect of acute hypercholesterolemia on myocardial infarct size and the no-reflow phenomenon during coronary occlusion-reperfusion. Circulation. 1987;75:292-298.
2.
Golino P, Maroko PR, Carew TE. Efficacy of
platelet depletion in counteracting the detrimental effect of acute
hypercholesterolemia on infarct size and the
no-reflow phenomenon in rabbits undergoing coronary artery
occlusion-reperfusion. Circulation. 1987;76:173-180.
3. Osborne JA, Lento PH, Siegfried MR, Stahl GL, Fusman B, Lefer AM. Cardiovascular effects of acute hypercholesterolemia in rabbits: reversal with lovastatin treatment. J Clin Invest. 1989;83:465-473.
4. Hoshida S, Nishida M, Yamashita N, Igarashi J, Hori M, Kamada T, Kuzuya T, Tada M. Amelioration of severity of myocardial injury by a nitric oxide donor in rabbits fed a cholesterol-rich diet. J Am Coll Cardiol. 1996;27:902-909.[Abstract]
5.
Jayakody L, Senaratne M, Thomson A, Kappagoda
T. Endothelium-dependent relaxation in
experimental atherosclerosis in the rabbit.
Circ Res. 1987;60:251-264.
6.
Osborne JA, Siegman MJ, Sedar AW, Mooers SU, Lefer
AM. Lack of endothelium-dependent relaxation in
coronary resistance arteries of cholesterol-fed
rabbits. Am J Physiol. 1989;256:C591–C597.
7. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991;338:1546-1550.[Medline] [Order article via Infotrieve]
8. Leung W-H, Lau C-P, Wong C-K. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolaemic patients. Lancet. 1993;341:1496-1500.[Medline] [Order article via Infotrieve]
9.
Mugge A, Elwell JH, Peterson TE, Hofmeyer TG, Heistad
DD, Harrison DG. Chronic treatment with polyethylene-glycolated
superoxide dismutase partially restores
endothelium-dependent vascular relaxations in
cholesterol-fed rabbits. Circ Res. 1991;69:1293-1300.
10. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993;91:2546-2551.
11.
Ohara Y, Peterson TE, Sayegh HS, Subramanian RR, Wilcox
JN, Harrison DG. Dietary correction of
hypercholesterolemia in the rabbit normalizes
endothelial superoxide anion
production. Circulation. 1995;92:898-903.
12. Verlangieri AJ, Bush MJ. Effects of d-alpha-tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr. 1992;11:131-138.[Abstract]
13. Shaish A, Daugherty A, O'Sullivan F, Schonfeld G, Heinecke JW. Beta-carotene inhibits atherosclerosis in hypercholesterolemic rabbits. J Clin Invest. 1995;96:2075-2082.
14.
Hodis HN, Mack WJ, LaBree L. Serial
coronary angiographic evidence that antioxidant vitamin intake
reduces progression of coronary artery
atherosclerosis. JAMA. 1995;273:1849-1854.
15. Steinberg D. Studies on the mechanism of action of probucol. Am J Cardiol. 1986;57:16H–21H.[Medline] [Order article via Infotrieve]
16. Gotoh N, Shimazu K, Komuro E, Tsuchiya J, Noguchi N, Niki E. Antioxidant activities of probucol against lipid peroxidations. Biochim Biophys Acta. 1992;1128:147-154.[Medline] [Order article via Infotrieve]
17.
Kita T, Nagano Y, Yokode M, Ishii K, Kume N, Ooshima A,
Yoshida H, Kawai C. Probucol prevents the progression of
atherosclerosis in Watanabe heritable
hyperlipidemic rabbit, an animal model for familial
hypercholesterolemia. Proc Natl
Acad Sci U S A. 1987;84:5928-5931.
18.
Carew TE, Schwenke DC, Steinberg D.
Antiatherogenic effect of probucol unrelated to its
hypocholesterolemic effect: evidence that antioxidants
in vivo can selectively inhibit low density lipoprotein degradation in
macrophage-rich fatty streaks and slow the progression of
atherosclerosis in the Watanabe heritable
hyperlipidemic rabbit. Proc Natl Acad Sci
U S A. 1987;84:7725-7729.
19.
Murohara T, Scalia R, Lefer AM.
Lysophosphatidylcholine promotes P-selectin expression in platelets
and endothelial cells: possible involvement of protein
kinase C activation and its inhibition by nitric oxide donors.
Circ Res. 1996;78:780-789.
20. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470-475.[Abstract]
21. Bucolo G, David H. Quantitative determinations of serum triglycerides by the use of enzymes. Clin Chem. 1973;19:476-482.[Abstract]
22.
Mao SJT, Yates MT, Parker RA, Chi EM, Jackson
RL. Attenuation of atherosclerosis in a modified
strain of hypercholesterolemic Watanabe rabbits with
the use of a probucol analogue (MDL 29,311) that does not lower serum
cholesterol. Arterioscler Thromb. 1991;11:1266-1275.
23.
Stocker R, Bowry VW, Frei B. Ubiquinol-10
protects human low density lipoprotein more efficiently against lipid
peroxidation than does alpha-tocopherol. Proc
Natl Acad Sci U S A. 1991;88:1646-1650.
24.
Hoshida S, Yamashita N, Igarashi J, Nishida M, Hori M,
Kamada T, Kuzuya T, Tada M. Nitric oxide synthase protects the
heart against ischemia-reperfusion injury in rabbits.
J Pharmacol Exp Ther. 1995;274:413-418.
25. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol. 1982;78:206-209.[Medline] [Order article via Infotrieve]
26. Hoshida S, Kuzuya T, Nishida M, Yamashita N, Hori M, Kamada T, Tada M. Ebselen protects against ischemia-reperfusion injury in a canine model of myocardial infarction. Am J Physiol. 1994;367:H2342–H2347.
27. Hoshida S, Kuzuya T, Yamashita N, Nishida M, Kitahara S, Hori M, Kamada T, Tada M. Gamma-glutamylcysteine ethyl ester for myocardial protection in dogs during ischemia and reperfusion. J Am Coll Cardiol. 1994;24:1391-1397.[Abstract]
28. Hoshida S, Nishida M, Yamashita N, Igarashi J, Aoki K, Hori M, Kuzuya T, Tada M. Heme oxygenase-1 expression and its relation to oxidative stress during primary culture of cardiomyocytes. J Mol Cell Cardiol. 1996;28:1845-1855.[Medline] [Order article via Infotrieve]
29.
Nishida M, Kuzuya T, Hoshida S, Kim Y, Kitabatake A,
Kamada T, Tada M. Polymorphonuclear leukocytes induced
vasoconstriction in isolated canine coronary arteries.
Circ Res. 1990;66:253-258.
30. Weyrich AS, Ma X-I, Lefer DJ, Albertine KH, Lefer AM. In vivo neutralization of P-selectin protects feline heart and endothelium in myocardial ischemia and reperfusion injury. J Clin Invest. 1993;91:2620-2629.
31.
Henriksen T, Mahoney EM, Steinberg D. Enhanced
macrophage degradation of low density lipoprotein previously
incubated with cultured endothelial cells: recognition
by receptor for acetylated low density lipoproteins.
Proc Natl Acad Sci U S A. 1981;78:6499-6503.
32.
Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL,
Steinberg D. Modification of low density lipoprotein by
endothelial cells involves lipid peroxidation and
degradation of low density lipoprotein phospholipids.
Proc Natl Acad Sci U S A. 1984;81:3883-3887.
33.
Quinn MT, Parthasarathy S, Fong LG, Steinberg D.
Oxidatively modified low density lipoproteins: a potential role in
recruitment and retention of monocyte/macrophages during
atherogenesis. Proc Natl Acad Sci U S A. 1987;84:2995-2998.
34. Parthasarathy S, Young SG, Witztum JL, Pittman RC, Steinberg D. Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest. 1986;77:641-644.
35. Sasahara M, Raines EW, Chait A, Carew TE, Steinberg D, Wahl PW, Ross R. Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol, I: is the extent of atherosclerosis related to resistance of LDL to oxidation? J Clin Invest. 1994;94:155-164.
36. Naruszewicz M, Carew TE, Pittman RC, Witztum JL, Steinberg D. A novel mechanism by which probucol lowers low density lipoprotein levels demonstrated in the LDL receptor-deficient rabbit. J Lipid Res. 1984;25:1206-1213.[Abstract]
37.
Clozel J-P, Lengsfeld H, Kuhn H, Baumgartner HR.
Decreased coronary vascular reserve in Watanabe heritable
hyperlipidemic rabbits.
Arteriosclerosis. 1988;8:310-320.
38. Ragazzi E, Chinellato A, DeBiasi M, Pandolfo L, Prosdocimi M, Norido F, Caparrotta L, Fassina G. Endothelium-dependent relaxation, cholesterol content and high energy metabolite balance in Watanabe hyperlipidemic rabbit aorta. Atherosclerosis. 1989;80:125-134.[Medline] [Order article via Infotrieve]
39.
Tagawa H, Tomoike H, Nakamura M. Putative
mechanisms of the impairment of endothelium dependent
relaxation of the aorta with atheromatous plaque in
heritable hyperlipidemic rabbits. Circ
Res. 1991;68:330-337.
40.
Rubanyi GM, Vanhoutte PM. Superoxide anions and
hyperoxia inactivate endothelium-derived
relaxing factor. Am J Physiol. 1986;250:H822–H827.
41. Keaney JF Jr, Xu A, Cunningham D, Jackson T, Frei B, Vita JA. Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. J Clin Invest. 1995;95:2520-2529.
42. Kugiyama K, Kerns SA, Morrisett JD, Roberts R, Henry PD. Impairment of endothelium-dependent arterial relaxation by lysolecithin in modified low-density lipoproteins. Nature. 1990;344:160-162.[Medline] [Order article via Infotrieve]
43. Chin JH, Azhar S, Hoffman BB. Inactivation of endothelium-derived relaxing factor by oxidized lipoproteins. J Clin Invest. 1992;89:10-18.
44. Bridges AB, Scott NA, Belch JJF. Probucol, a superoxide free radical scavenger in vitro. Atherosclerosis. 1991;89:263-265.[Medline] [Order article via Infotrieve]
45.
Girerd XJ, Hirsch AT, Cooke JP, Dzau VJ, Creager
MA. L-Arginine augments
endothelium-dependent vasodilation in
cholesterol-fed rabbits. Circ Res. 1990;67:1301-1308.
46.
Jolly SR, Kane WJ, Bailie MB, Abrams GD, Lucchesi
BR. Canine myocardial reperfusion injury: its reduction by the
combined administration of superoxide dismutase and catalase.
Circ Res. 1984;54:277-285.
47.
Opie LH. Reperfusion injury and its
pharmacologic modification. Circulation. 1989;80:1049-1062.
48. Kuzuya T, Hoshida S, Nishida M, Kim Y, Fuji H, Kitabatake A, Kamada T, Tada M. Role of free radicals and neutrophils in canine myocardial reperfusion injury: myocardial salvage by a novel free radical scavenger, 2-octadecylascorbic acid. Cardiovasc Res. 1989;23:323-330.[Medline] [Order article via Infotrieve]
49. Lucchesi BR. Modulation of leukocyte-mediated myocardial reperfusion injury. Annu Rev Physiol. 1990;52:561-576.[Medline] [Order article via Infotrieve]
50. Buerke M, Weyrich AS, Zheng Z, Gaeta FCA, Forrest MJ, Lefer AM. Sialyl Lewisx-containing oligosaccharide attenuates myocardial reperfusion injury in cats. J Clin Invest. 1994;93:1140-1148.
51.
Hahne M, Jager U, Isenmann S, Hallmann R, Vestweber
D. Five tumor necrosis factor-inducible cell adhesion mechanisms
on the surface of mouse endothelioma cells mediate the binding of
leukocytes. J Cell Biol. 1993;121:655-664.
52.
Patel KD, Zimmerman GA, Prescott, SM, McEver RP,
McIntyre TM. Oxygen radicals induce human
endothelial cells to express GMP-140 and bind
neutrophils. J Cell Biol. 1991;112:749-759.
53. Lehr H-A, Olofsson AM, Carew TE, Vajkoczy P, von Andrian UH, Hubner C, Berndt MC, Steinberg D, Messmer K, Arfors KE. P-selectin mediates the interaction of circulating leukocytes with platelets and microvascular endothelium in response to oxidized lipoprotein in vivo. Lab Invest. 1994;71:380-386.[Medline] [Order article via Infotrieve]
54.
Gauthier TW, Davenpeck KL, Lefer AM. Nitric
oxide attenuates leukocyte-endothelial interaction via
P-selectin in splanchnic ischemia-reperfusion.
Am J Physiol. 1994;267:G562–G568.
55.
Cybulsky MI, Gimbrone MA Jr.
Endothelial expression of a mononuclear leukocyte
adhesion molecule during atherogenesis. Science. 1991;251:788-791.
56. Poston RN, Haskard DO, Coucher JR, Gall NP, Johnson-Tidey RR. Expression of intercellular adhesion molecule-1 in atherosclerotic plaques. Am J Pathol. 1992;140:665-673.[Abstract]
57. van der Wal AC, Das PK, Tigges AJ, Becker AE. Adhesion molecules on the endothelium and mononuclear cells in human atherosclerotic lesions. Am J Pathol. 1992;141:1427-1433.[Abstract]
58. O'Brien KD, Allen MD, McDonald TO, Chait A, Harlan JM, Fishbein D, McCarty J, Ferguson M, Hudkins K, Benjamin CD, Lobb R, Alpers CE. Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques: implications for the mode of progression of advanced coronary atherosclerosis. J Clin Invest. 1993;92:945-951.
59. Calderon TM, Factor SM, Hatcher VB, Berliner JA, Berman JW. An endothelial cell adhesion protein for monocytes recognized by monoclonal antibody IG9: expression in vivo in inflamed human vessels and atherosclerotic human and Watanabe rabbit vessels. Lab Invest. 1994;70:836-849.[Medline] [Order article via Infotrieve]
60. Watanabe Y, Ito T, Shiomi M. The effect of selective breeding on the development of coronary atherosclerosis in WHHL rabbits, an animal model for familial hypercholesterolemia. Atherosclerosis. 1985;56:71-79.[Medline] [Order article via Infotrieve]
61. Hatanaka K, Ito T, Shiomi M, Yamamoto A, Watanabe Y. Ischemic heart disease in the WHHL rabbit: a model for myocardial injury in genetically hyperlipidemic animals. Am Heart J. 1987;113:280-288.[Medline] [Order article via Infotrieve]
62. Maxwell MP, Hearse DJ, Yellon DM. Species variation in the coronary circulation during regional myocardial ischemia: a critical determinant of the rate of evolution and extent of myocardial infarction. Cardiovasc Res. 1987;21:737-746.[Medline] [Order article via Infotrieve]
63. Gey KF, Puska P, Jordan P, Moser UK. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr. 1991;53(suppl 1):3265-3345.
64. Gaziano JM, Hennekens CH. The role of beta-carotene in the prevention of cardiovascular disease. In: Canfield LM, Krinsky NI, Olson JA, eds. Carotenoids in Human Health. New York, NY: New York Academy of Sciences; 1993:148-155.
65. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ, Brown MJ. Randomised controlled trial of vitamine E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781-786.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. Hori and K. Nishida Oxidative stress and left ventricular remodelling after myocardial infarction Cardiovasc Res, February 15, 2009; 81(3): 457 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Li, S. Tokuno, P. Tahepold, J. Vaage, C. Lowbeer, and G. Valen Preconditioning protects the severely atherosclerotic mouse heart Ann. Thorac. Surg., April 1, 2001; 71(4): 1296 - 1303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hoshida, N. Yamashita, K. Otsu, T. Kuzuya, and M. Hori Cholesterol feeding exacerbates myocardial injury in Zucker diabetic fatty rats Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H256 - H262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hoshida, N. Yamashita, K. Kawahara, T. Kuzuya, and M. Hori Amelioration by Quinapril of Myocardial Infarction Induced by Coronary Occlusion/Reperfusion in a Rabbit Model of Atherosclerosis : Possible Mechanisms Circulation, January 26, 1999; 99(3): 434 - 440. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||