Download Mobilization of Antioxidant Vitamin Pools and

Mobilization of Antioxidant Vitamin Pools and
Hemodynamic Function After Myocardial Infarction
Vince P. Palace, PhD; Mike F. Hill, PhD; Firoozeh Farahmand, MD; Pawan K. Singal, PhD, DSc
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Background—Although most previous studies have attempted to correlate plasma concentrations of vitamins with specific
cardiovascular end points, metabolic considerations suggest that changes in myocardial tissue and storage organs may
be better indicators of myocardial oxidative stress.
Methods and Results—Rats fed commercial chow or a diet enriched with vitamin E for 2 weeks were subjected to either
a surgical myocardial infarction (MI) or a sham procedure. Rats were hemodynamically assessed 16 weeks after surgery,
and their heart, liver, kidney, and plasma were analyzed for antioxidant vitamins E (tocopherol) and A (retinol and total
retinyl esters). At 16 weeks, MI rats on a control diet showed depressed peak systolic and elevated diastolic pressures
in both right and left ventricles compared with their sham controls. Plasma concentrations of vitamins E and A in MI
rats were not different from sham controls fed the same diet. However, concentrations of vitamin E in left ventricle and
liver and of vitamin A in liver (retinol) and kidney (retinyl esters) were decreased in rats with MI compared with the
sham controls. Vitamin E supplementation improved hemodynamic function in rats with MI and increased plasma,
myocardial, liver, and kidney concentrations of vitamin E. The vitamin E diet also prevented the loss of total retinyl
esters from the kidney but not of retinol from the liver in MI rats.
Conclusions—Dietary supplements of vitamin E can sustain better cardiac function subsequent to MI. Antioxidant vitamin
levels in the myocardium or in storage organs and not in plasma may be better indicators of myocardial oxidative stress.
(Circulation. 1999;99:121-126.)
Key Words: heart failure n free radicals n myocardial infarction n antioxidants
and kidney, are thought to function as reservoirs.12,13 Therefore, potential increases in the utilization of antioxidant
vitamins in the heart and plasma after a disruptive cardiac
event may be buffered by mobilization of vitamins from other
larger storage pools in the body. In fact, in animals exposed
to chemicals that alter vitamin A metabolism, liver and
kidney have been reported to be more sensitive indicators of
vitamin A status than serum concentrations.14
In the present study, antioxidant vitamin E and A concentrations in the plasma, myocardium, liver, and kidney were
measured in hemodynamically assessed rats with or without
myocardial infarction (MI). The effects of dietary vitamin E
supplementation for 16 weeks on vitamin E and A status, as
well as hemodynamic function in these groups, were also
examined.
C
urrent interest in the antioxidant vitamins E and A as
they relate to heart disease has evolved from the growing
realization that free radical–mediated tissue damage is involved in the pathogenesis and progression of several forms
of cardiac dysfunction.1–3 Several large-scale epidemiological
studies have recently shown an inverse relationship between
vitamin E and A consumption and the risk of cardiovascular
disease.4,5 Furthermore, experimental evidence has shown
depletion of these antioxidant vitamins in different cardiac
abnormalities.6 –9 However, there is also experimental evidence suggesting that plasma and/or myocardial concentrations of vitamins E and A are not related to oxidative stress or
depressed cardiac function.10,11 Clearly, more work is required
to clarify the role of antioxidant vitamins in heart failure.
In the majority of past studies, plasma was the target site
for analysis of vitamin concentrations. A few studies have
also considered vitamin concentrations specifically in heart
tissue.9 The myocardium and resident blood plasma are
certainly expected to be the tissues initially affected by free
radical production during cardiac disturbances. However, the
heart contains only a small proportion of the body’s total
antioxidant vitamin pool. Larger stores, present in the liver
Methods
Animals and Surgical Treatment
Male Sprague-Dawley rats (12567 g; n560), housed in pairs, were
randomly assigned to either a basal diet (rat chow, PMI feeds) or a
vitamin E– enriched diet (1545 mg of tocopherol acetate per kilogram of feed). After 2 weeks on these diets, each group was further
Received May 12, 1998; revision received August 21, 1998; accepted September 3, 1998.
From the Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, Faculty of Medicine,
University of Manitoba, Winnipeg, Canada.
Correspondence to Dr Pawan K. Singal, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, 351 Tache Ave, Room
3022, Winnipeg, Manitoba R2H 2A6, Canada. E-mail [email protected]
© 1999 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
121
122
Antioxidant Vitamins After MI
subdivided into an MI and a sham group (n515 each). Rats in the MI
groups were anesthetized and underwent surgery to ligate the left
coronary artery, as described previously.9 Using this surgical procedure, we have previously shown that an infarct is produced that
reaches #50% of the left ventricle. To reduce variability due to
differences in infarct size, rats with infarcts of ,20% of the left
ventricular mass were not included in the present study.15 Rats in the
control groups underwent the same procedure, except that the suture
was not tied around the coronary artery. After recovering from the
procedures, rats were kept on diets identical to their presurgical
grouping for an additional 16 weeks.
At the end of 16 weeks, animals were anesthetized with sodium
pentobarbital (50 mg/kg IP), and their left and right ventricular
functions were assessed by a miniature pressure transducer.9 After
these assessments, animals were killed, and the heart, liver, and
kidney were removed and immediately frozen in liquid nitrogen.
Plasma was isolated from whole blood by centrifugation and
similarly frozen.
All of the animals used in the present study were maintained and
treated in accordance with the policies and procedures of the
Canadian Council on Animal Care.
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Vitamin Measurement
Vitamin E (tocopherol) and vitamin A (retinol and retinyl esters)
were measured in the myocardium, liver, kidney, and plasma, as well
as in the feed, by use of an extraction procedure and reverse-phase
high-performance liquid chromatography (HPLC) detection
method.16
Synthesis and Structural Confirmation of
Vitamin A Esters
Because only the palmitate ester of Vitamin A is commercially
available, HPLC standards for other vitamin A esters were synthesized by use of a modification of a cholesterol ester synthesis
method. All preparatory steps were performed under subdued light
conditions and in amber vials. Briefly, 2020 nmol of vitamin A
(retinol) suspended in toluene was placed by means of a pipette into
a vial that contained 6060 nmol of the appropriate lipid anhydride,
also suspended in toluene. Contents of the vial were thoroughly
mixed. Each sample was completely dried under vacuum in a rotary
evaporator at room temperature, purged with nitrogen, tightly
capped, and incubated in the dark at 68°C in a water bath for 8 to 12
hours. Samples were then resuspended in HPLC mobile phase and
analyzed by the HPLC method.16 Retention times for each unknown
ester were established, and post-HPLC eluant fractions corresponding to these intervals were collected and dried under vacuum. After
suspension in the HPLC mobile phase, the samples were eluted by
the same HPLC separation procedure. Each eluant corresponding to
a vitamin A ester peak retention time was analyzed by mass
spectrometry to confirm the vitamin A ester in that peak.
Data Analysis
All data are presented as mean6SEM. Group means were analyzed
by ANOVA followed by Bonferroni pairwise t tests to identify
differences between specific means. Statistical significance was set
at P,0.05.
Results
Hemodynamics
Results from the hemodynamic assessments of right and left
ventricles from the 4 groups are summarized in the Table.
Animals fed the basal diet in the 16-week post-MI group
showed an elevation in left-ventricular end-diastolic pressure
and a depression of left-ventricular peak systolic pressure
compared with control rats fed the same diet. A similar
pattern of pressure changes was present in the right ventricle.
Control animals fed the diet supplemented with vitamin E
Hemodynamic Parameters of Rats Fed Basal or Vitamin
E–Enriched Diet and Subjected to Surgical MI or a
Sham Procedure
Group
Basal diet sham
Basal diet MI
Vitamin E diet sham
Vitamin E diet MI
LVEDP,
mm Hg
2.360.6
28.160.8*
3.861.7
13.561.7*†
LVPSP,
mm Hg
128.361.8
83.662.3*
RVEDP,
mm Hg
RVPSP,
mm Hg
1.560.5
30.461.7
9.160.9*
17.460.4*
130.862.2
2.660.8
38.363.4
108.566.8*†
2.861.3†
34.162.6†
LVEDP indicates left-ventricular end-diastolic pressure; LVPSP, left-ventricular peak systolic pressure; RVEDP, right-ventricular end-diastolic pressure;
and RVPSP, right-ventricular peak systolic pressure.
All function studies were done 16 weeks after surgery. Data are mean6SEM
(n56, except basal diet MI group, where n58).
*Significantly (P,0.05) different from sham control group receiving the
same diet.
†Significantly (P,0.05) different from basal diet MI group.
showed no change in any of their hemodynamic parameters
compared with animals on the basal diet. Vitamin E feeding
significantly attenuated the rise in left-ventricular end-diastolic pressure as well as the drop in left-ventricular peak
systolic pressure in the MI group, but both of the values were
significantly different from control levels. Values for the right
ventricle (end-diastolic and peak systolic pressures) in the
vitamin E–supplemented MI group were maintained near
control levels.
Vitamin E Consumption and
Tissue Concentrations
Vitamin E content was 40.661.4 mg/kg in the basal diet and
15456101 mg/kg in the enriched diet. Analysis of each diet
at the beginning and end of the experiment determined that
loss of vitamin E was ,4% and was not significantly
different between any batch of the diet preparations. There
were no significant differences in the intake of vitamin E per
day between the 2 basal diet groups (sham51.1560.02 mg/d
per animal; MI51.1160.04 mg/d per animal) or the
enriched-diet groups (sham532.5361.03 mg/d per animal;
MI532.0360.9 mg/d per animal).
Vitamin E concentrations in plasma, left ventricle, right
ventricle, liver, and kidney are shown in Figure 1. Vitamin E
concentration was highest in the liver and left and right
ventricles, followed by kidney and plasma. MI depleted
tocopherol in the left ventricles by .32% and in the liver by
37% in rats fed the basal diet compared with their sham
controls. MI in rats fed the basal diet had no effect on vitamin
E levels in the plasma, right ventricle, or kidney.
The vitamin E– enriched diet significantly (P,0.05) elevated concentrations of the vitamin in all of the tissues from
sham animals (Figure 1). The maximum percent increase was
in the liver (340%), followed by plasma (250%), both
ventricles (60%), and kidney (26%). A significant gain in
vitamin E concentrations was also seen in all of the tissues in
the supplemented MI animals. However, in the MI animals,
left ventricular vitamin E concentration was significantly less
(225%) than the sham controls supplemented with vitamin E.
There was a trend toward lower vitamin E concentrations in
the liver of MI rats fed the enriched diet compared with their
Palace et al
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Figure 1. Vitamin E (Vit. E) in plasma (P), left ventricle (LV), right
ventricle (RV), liver (L), and kidney (K) of rats fed a basal or vitamin E– enriched diet. All animals were subjected to either surgical MI or sham (control) procedures. Data are mean6SEM of 5
animals. Statistical differences (P,0.05) from sham controls of
same diet treatment are denoted by *, and those between diet
groups with the same surgical treatment are denoted by †. Note
that the scale for concentration (vertical axis) given on the left is
different for each tissue.
diet controls, but the difference was not statistically
significant.
Tissue Concentrations of Vitamin A (Retinol and
Total Retinyl Esters)
Using synthesized and authenticated vitamin A ester standards, we performed analyses of different vitamin A esters
in the heart, liver, kidney, and plasma tissues from rats fed
the basal and enriched diets. Retinol was present in all
tissues (liver.kidney..LV, RV, and plasma). At least 5
retinyl esters were routinely detected in the liver
(palmitate..stearate.oleate .linoleate.octanoate), 3 in the
kidney (palmitate..stearate.octanoate), and only 1 (palmitate) in the plasma and the heart. Although retinyl palmitate
was detectable in plasma and in both the right and left
ventricles, its concentration was highly variable and was
generally ,0.002 nmol/g.
Retinol concentrations in the plasma, left ventricle, right
ventricle, liver, and kidney are shown for all 4 experimental
groups in Figure 2. Plasma retinol concentrations were
unaffected by MI. Sham and MI rats fed the vitamin E– enriched diet had significantly higher concentrations of retinol
in plasma than their respective basal diet controls. Neither
January 5/12, 1999
123
Figure 2. Effects of MI on retinol in plasma (P), left ventricle
(LV), right ventricle (RV), liver (L), and kidney (K) of rats fed a
basal or vitamin E (Vit. E)– enriched diet. All animals were subjected to surgery for either MI or sham control procedures. Data
are mean6SEM of 5 animals. Statistical differences (P,0.05)
from sham controls of same diet treatment are denoted by *,
and those between diet groups with same surgical treatment are
denoted by †. Note that the vertical scale given on the left is
different for each tissue.
dietary vitamin E supplements nor MI had any effect on left
or right ventricular retinol concentrations. MI depleted liver
retinol by 34% in rats fed the basal diet compared with their
sham controls, and this depletion was not significantly
attenuated by vitamin E supplementation. Kidney retinol
concentrations were unaffected by MI or vitamin E
supplementation.
Total retinyl esters are shown only for liver and kidney
(Figure 3). Retinyl ester concentrations in plasma and myocardial tissue are not given because of their low values and
high variability. Liver retinyl ester concentrations were not
significantly different in the control and MI groups maintained on the basal diet. The vitamin E– enriched diet significantly increased retinyl esters in both control and MI groups.
Retinyl ester concentrations significantly declined after MI in
the kidneys of rats fed the basal diet compared with their
sham controls, but these differences were not evident between
the vitamin E– enriched, control, and MI groups.
Discussion
Antioxidants and Heart Failure: Cause and Effect
Previously, we9 reported that heart failure subsequent to MI in
rats correlated with a decrease in antioxidant enzymes,
catalase, and glutathione peroxidase, as well as an increase in
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Antioxidant Vitamins After MI
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Figure 3. Effects of MI on total retinyl esters in liver (L) and kidney (K) of rats fed a basal or vitamin E (Vit. E)– enriched diet. All
animals were subjected to surgery for either MI or sham control
procedures. Data are mean6SEM of 5 animals. Statistical differences (P,0.05) from sham controls of same diet treatment are
denoted by *, and those between diet groups with same surgical treatment are denoted by †. Note that the vertical scale
given on the left is different for each tissue.
oxidative stress. In the present study, depressed left ventricular function in the MI rats was also associated with a
decrease in the nonenzymatic antioxidant vitamin E. There
are now many experimental9,17–19 and clinical20 –22 studies
documenting a close relationship between antioxidant deficit
and cardiac dysfunction. In the present study, a diet supplemented with vitamin E improved endogenous levels of this
vitamin and modulated the decline in cardiac function in the
MI group. These data clearly demonstrate that an increase in
myocardial antioxidant concentrations helps sustain cardiac
function subsequent to MI, thus suggesting that a decrease in
antioxidant reserve may be a causative factor.
Antioxidant Dynamics: Tissue and
Plasma Concentrations
The heart contains a relatively small fraction of the total
antioxidant vitamin complement in the body. Any depletion
of vitamins (E and A) in the heart tissue or plasma may be
buffered by mobilization of these vitamins from the other
large storage pools.23 How vitamins E and A are absorbed in
the gut and reach the heart, liver, and kidney through the
plasma is shown in Figure 4. Unlike vitamin A, vitamin E
concentrations in the plasma are not tightly regulated by a
specific transport protein, and they may fluctuate significantly.24 However, the liver still plays an important role in the
distribution of vitamin E to extrahepatic tissues, including the
heart. The present study highlights the importance of monitoring tissue rather than plasma content of vitamins to detect
the relationship with cardiac events. It is obvious that obtaining tissue samples to assess antioxidant vitamin content is not
practical in a clinical setting. In this regard, at least 2 studies
have recently shown that short-term peaks of vitamin A in the
plasma, after an administered dose, can be used to calculate
liver stores of the vitamin.25,26
Vitamin E Changes
Although concentrations of vitamin E were not different in
the plasma of rats subjected to MI, significant depletions of
this vitamin did occur in the myocardium and liver. It has
been reported that myocardial vitamin E concentrations
decline in response to disruptive cardiac events,27 including
MI.9 This decline probably reflects increased demand for the
vitamin due to elevated oxidative stress.9,28 Although the
percent decline in vitamin E in the left ventricle (32%) and
liver (37%) of rats with MI in the present study was
comparable, the liver, because of its larger size, suffered a
much higher net loss of vitamin E. Taking tissue weight into
account, the total loss of vitamin E in liver was 550 mg
compared with a 15-mg loss from the heart. Possibly, the
depletion of vitamin E from the liver occurs as the vitamin is
mobilized from this large storage pool to replenish the
depleted vitamin level in the oxidatively stressed left ventricle. Others29 have also noted the importance of the liver in
redistributing vitamin E to tissues with transitory higher
requirements.
In addition, our results show that by supplementing the diet
with vitamin E, myocardial and hepatic concentrations of
vitamin E can be elevated relative to baseline levels, even in
animals with surgical MI. It is likely that MI does not
influence vitamin E absorption at the gut level. Results from
the kidney suggest that this organ is not as important as the
liver for storing or supplying vitamin E to the heart after MI.
Vitamin A Changes
How the heart derives its retinol from the plasma and how
both the liver and kidney can release retinol from the
esterified forms when retinol binding protein (RBP) in the
plasma is unoccupied by the retinol ligand are shown in
Figure 4. In the current study, retinol concentrations in both
the plasma and left ventricular tissue were unaffected by MI.
However, liver retinol concentrations declined by 34% in rats
with surgical MI compared with sham control rats, representing a mean total loss of '60 mg of retinol after MI. This
depletion occurred despite an ample supply of vitamin A
from the commercial diet used in the present study (ie, 1160
IU/kg body weight per day). It has been reported20 that 50 000
IU/d of dietary vitamin A, which for a 75-kg person translates
to 667 IU/d per kilogram, given as a part of an antioxidant
therapy regimen, was effective in reducing oxidative stress
and infarct size in patients with suspected MI. The relatively
high supply in the basal diet in the present study may have
contributed to the fact that storage forms of vitamin A, ie,
total retinyl esters, were not significantly depleted in the liver
of MI rats.
In contrast to the liver, total retinyl esters (ie, retinyl
octanoate plus retinyl palmitate plus retinyl stearate) in the
kidney declined significantly. The kidneys contribute a significant amount of retinol to the plasma by recapturing retinol
and RBP that are not bound to transthyretin (TTR) and are
therefore small enough to be filtered through the glomerulus.30 The recaptured retinol is either esterified or bound to
RBP for reentry to the plasma pool. Actually, newly acquired
retinol is preferentially esterified over resident intracellular
retinol.31 Delivery of retinol by the complete plasma transport
complex (retinol-RBP-TTR) appears to be important for this
process, at least in liver stellate cells.32 The kidney is also
known to contain stellate cells.33 Because kidneys maintain
Palace et al
January 5/12, 1999
125
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Figure 4. Vitamin E and A uptake and
the major organ-delivery pathways.
Retinyl esters (Re) and most of the
b-carotene in the diet are enzymatically
hydrolyzed to retinol in the lumen of the
small intestine before being taken up
by brush border cells (BBCs).
b-Carotene that is taken up directly
from the lumen is also largely converted to retinol inside BBCs. Retinol is
then esterified and packaged into chylomicron particles by BBCs. Vitamin E
passively diffuses into BBCs and also
enters chylomicrons. Chylomicron particles are exported to the lymphatic system and join the general circulation,
where they are partially degraded by
the enzyme systems of endothelial cells
to yield chylomicron remnants. Recognition of the chylomicron remnants by
liver parenchymal cells is receptor
mediated and results in uptake of both
vitamin E and retinyl esters. In liver
parenchymal cells, retinyl esters are
hydrolyzed, and liberated retinol can be
bound to RBP for export to plasma or
delivered to stellate cells, where it is
reesterified and stored as retinol esters.
Retinol in plasma is associated with its
binding protein, and in its bound form
complexes with another plasma protein,
TTR. The entire complex serves as a
vehicle for delivering retinol to virtually
all other tissues of the body, including
heart. Retinyl esters can be hydrolyzed
and released from kidney in the same
way. In liver cells, vitamin E derived
from remnants is either bound to an
intracellular binding protein or packaged into lipoprotein particles ( ç ) for
export to plasma. Exchange of vitamin
E occurs between target organ cells
and various types of lipoprotein
particles.
retinol concentrations by scavenging retinol through the
glomerulus in a form that can be preferentially esterified by
the kidney stellate cells, this process may be compromised
after MI.
Supplementation with dietary vitamin E elevated plasma
concentrations of vitamin A and allowed kidney vitamin A
esters to return to baseline, even after MI. These effects are
almost certainly related to the fact that vitamins E and A are
complimentary antioxidants, such that supplementation with
vitamin E spares vitamin A.34 Retinol has been shown to be an
effective peroxyl radical scavenger. In fact, it may be even
more effective than tocopherol, by virtue of its shorter
polyene chain that affords it increased mobility and better
access to peroxyl radicals in the membrane.35 However, the
ability of retinol to scavenge aqueous initiator species is far
below that of tocopherol owing to the fact that it lacks a
hydroxyl group at the membrane surface.35 Rats supplemented with vitamin E still had lower vitamin A in the liver
after MI, which suggests that this organ may experience
different stresses on its vitamin A pool and its handling
capabilities after MI.36
Conclusions
Results from this study suggest that analysis of plasma as the
sole indicator of vitamin status may not yield accurate
information because this vector is affected much later in the
evolution of heart failure, when storage-organ concentrations
are depleted. Analyses of antioxidants in storage organs,
therefore, offers a more reliable indication of antioxidant
consumption after disruptive cardiac events. Furthermore,
dietary supplements of vitamin E increase storage-organ
concentrations of vitamins E and A and maintain cardiac
126
Antioxidant Vitamins After MI
function, even after MI. Although it is clear that storageorgan concentrations are an important part of antioxidant
vitamin homeostasis, additional studies are required to elucidate their exact kinetic relationships.
Acknowledgments
This work was supported by a grant from the Medical Research
Council of Canada to the Group in Experimental Cardiology (Dr
Singal). Dr Singal is a career investigator of the Medical Research
Council of Canada. Dr Palace and Mr Hill were supported by
fellowships from the Manitoba Health Research Council.
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Mobilization of Antioxidant Vitamin Pools and Hemodynamic Function After Myocardial
Infarction
Vince P. Palace, Mike F. Hill, Firoozeh Farahmand and Pawan K. Singal
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