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(Circulation. 1995;91:1123-1128.)
© 1995 American Heart Association, Inc.
Articles |
Fish Oil Treatment Decreases Superoxide Anions in the Myocardium and Coronary Arteries of Atherosclerotic Monkeys
Presented in part at the 68th Scientific Sessions of the American Heart Association, November 8-11, 1993, Atlanta, Ga, and published in abstract form (Circulation. 1993;88[suppl I]:I-466).
From the Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC (J.K.W.); Indonesian Cardiac Center, Jakarta, and Institut Perranian Bogor (Indonesia) (F.S., T.U.); and Emory University School of Medicine, Atlanta, Ga (D.G.H.).
Correspondence to J. Koudy Williams, DVM, Department of Comparative Medicine, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1040.
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Abstract |
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Background This experiment sought to determine the effects of fish oil on superoxide anion production in the myocardium and coronary arteries of atherosclerotic monkeys. Recent evidence indicates that dietary supplementation with fish oil preserves normal vasomotion of atherosclerotic coronary arteries and reduces damage to the myocardium after ischemia and reperfusion, although the mechanisms remain unclear.
Methods and Results Adult male cynomolgus monkeys were fed an atherogenic diet with (n=15) or without (n=15) half the fat calories from fish oil. After 12 months, chemiluminescence of lucigenin was used to measure superoxide anion production in coronary arteries and myocardium after 1 hour of ischemia and 2 hours of reperfusion. The signals were calibrated with known quantities of xanthine and xanthine oxidase. Superoxide anion production in ischemic myocardium was (mean±SEM, nmol/mg dry wt per minute) 1±1 and 4±1 in monkeys fed fish oil and not fed fish oil, respectively (P<.05). Superoxide anion production in coronary arteries not exposed to ischemia and reperfusion was (nmol/mg dry wt per minute) 4±1 and 8±2 in monkeys fed fish oil and not fed fish oil, respectively (P<.05). Superoxide anion production in coronary arteries was (nmol/mg dry wt per minute) 5±2 and 16±3 in monkeys fed fish oil and not fed fish oil after ischemia and reperfusion, respectively (P<.05).
Conclusions Dietary supplementation with fish oil reduced vascular superoxide anion production and prevented the increase in vascular and myocardial superoxide anion production that accompanied ischemia and reperfusion. These phenomena may underlie some of the beneficial cardiovascular effects of fish oil.
Key Words: fatty acids • atherosclerosis • reperfusion • ischemia
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Consumption of diets rich in fish oil has been associated with a reduced risk of coronary artery disease.1 Effects of fish oil on risk factors for coronary heart disease are variable.2 3 4 5 However, recent evidence indicates that dietary supplementation with fish oil reduces infarct size after ischemia and reperfusion6 7 and promotes coronary artery dilator responses,8 although the mechanisms remain unclear.
It has been proposed that invasion of inflammatory cells into the
ischemic myocardium and the formation of oxygen free radicals during
reperfusion may promote myocardial damage.9 
-3 Fatty
acids from fish oil can reduce superoxide anion production by
inflammatory cells.10 However, there is no direct evidence
that fish oil decreases superoxide production in the myocardium.
Recently it was reported that atherosclerosis increases the production of vascular superoxide anions and may, through this mechanism, inactivate nitric oxide and impair endothelium-mediated dilation of arteries.11 Shimokawa et al8 concluded that fish oil improves endothelium-dependent coronary dilator responses, presumably through nitric oxide–mediated mechanisms. However, there is no direct evidence that fish oil reduces superoxide anion production in arteries. Therefore, the goals of this study were to determine whether dietary fish oil reduces basal levels of superoxide anion in the myocardium and coronary arteries and whether fish oil diminishes the increase in superoxide anion production associated with ischemia and reperfusion. Such effects on superoxide anion production may explain in part the beneficial effects of fish oil on infarct size and coronary vasomotion.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Experimental Design
Thirty adult male cynomolgus monkeys (Macaca fascicularis) were studied. The monkeys initially were housed at the Indonesian Primate Center in Bogor, Indonesia. The monkeys were fed an atherogenic diet containing 0.4 mg/cal cholesterol from egg yolk, 22% of calories from protein, 41% from fat (primarily beef tallow), and 37% from carbohydrate. The diet contained 43% saturated, 43% monounsaturated, and 14% polyunsaturated fat.
The monkeys consumed the
atherogenic diet for 2 months and were divided
into two groups (n=15 per group) with equivalent total plasma
cholesterol (TPC) and HDL cholesterol (HDLC) concentrations. The diet
of one group of monkeys was then changed so that one half the calories
from fat was supplied by fish oil (purified lemuru fish oil from
Indonesia; 18% eicosapentaenoic acid). The amount of fish oil fed to
the monkeys supplied 0.5 g/kg per day of eicosapentaenoic acid. Since
fish oil contains the antioxidant vitamin E (
-tocopherol),
-tocopherol was added to the diet without fish oil to equilibrate
vitamin E concentrations between diets. The diet containing fish oil
diet comprised 35% saturated, 36% monounsaturated, and 29%
polyunsaturated fat.
The monkeys consumed their test diets for 6 months and were then shipped from Indonesia to the Comparative Medicine Clinical Research Center at Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC. They were quarantined for 3 months according to regulations of the Centers for Disease Control. The monkeys continued to eat their test diets during this time and for an additional 3 months after the quarantine period (total test diet time, 12 months) and were then studied. All procedures involving animals were conducted in compliance with state and federal laws, standards of the US Department of Health and Human Services, and guidelines established by the Institutional Animal Care and Use Committee.
Measurement of Blood Pressure and Plasma Lipids
Every 3
months during the experiment, blood pressures were
measured with a model 8100 Dinamap Research Monitor12 and
blood samples were collected from tranquilized, fasted monkeys for
measurement of TPC,13 HDLC,14 and plasma
triglyceride concentrations.15 Plasma concentrations of
LDL cholesterol (LDLC) were determined indirectly by subtracting HDLC
from the TPC concentrations. Samples taken in Indonesia were measured
at the National Cardiac Center. Paired samples were sent to Bowman Gray
for analysis. The correlation between results obtained at the
National Cardiac Center and Bowman Gray was 0.90. Care was taken to
ensure that individual plasma lipid concentrations returned to the
levels measured in Indonesia at least 2 months before the monkeys were
studied at Bowman Gray. Fatty acid distribution in the plasma of the
monkeys was measured once, at the end of the dietary protocol just
before necropsy.16 Fatty acid composition of the diet was
measured by similar methods in Indonesia before the fish oil was sent
to Bowman Gray.
Experimental Protocol
On the day of the study, monkeys were
anesthetized with ketamine
hydrochloride (10 mg/kg IM) and sodium pentobarbital (30 mg/kg IV to
effect). An endotracheal tube was inserted, and the lungs were
ventilated with room air supplemented with 95% oxygen. Blood gases
were monitored and maintained within the normal range. Catheters were
inserted into the femoral artery for measurement of blood pressure and
heart rate and into the femoral vein for administration of drugs.
External patch leads were attached to the monkeys for monitoring the
lead II configuration of the ECG. A thoracotomy was done through the
fourth intercostal space, and the left side of the heart was exposed by
packing back the left lung lobes and incising the pericardial sac. The
left anterior descending coronary artery (LAD) was ligated distal to
the first diagonal branch with a 0-Dexon suture that occluded both the
artery and vein. Ligation was confirmed by lack of a pulse in the
distal LAD and the appearance of a bluish color in the affected
myocardium. The LAD was occluded for 1 hour, and the ligature was then
removed. Reperfusion was confirmed by detection of a pulse in the
distal LAD after removal of the ligature and by a return of more normal
color to the myocardium.
Two hours after the onset of reperfusion, the monkeys were euthanatized by sodium pentobarbital 80 mg/kg IV. The heart was quickly removed (within 30 seconds after the pentobarbital was administered) and placed in oxygenated, chilled (20°C) Krebs-HEPES buffer (pH 7.4).11 The entire length of the epicardial LAD was quickly and carefully dissected from the myocardium and placed in fresh room-temperature Krebs-HEPES buffer. The LAD was then divided perpendicular to the long axis into distal (exposed to ischemia and reperfusion) and proximal (used to measure levels of superoxide anion production in unmanipulated artery) segments. Each segment (proximal and distal) was divided perpendicular to the long axis into two ring segments, and one segment was denuded of luminal endothelium by gentle rubbing with a closed forceps. Removal of endothelium was confirmed by light microscopic evaluation of random samples taken throughout the experiment. Four artery samples were analyzed for each monkey: two proximal (denuded and nondenuded) and two distal (denuded and nondenuded).
Samples (1 g each) of myocardium were taken from the distal anterior wall (ischemic) and proximal posterior wall (nonischemic) of the left ventricle and placed in room-temperature Krebs-HEPES buffer. The 1-g samples of myocardium were each divided into 10 (0.1-g) samples, which were assayed for superoxide dismutase by chemiluminescence, and the results were reported as the mean counts of these 0.1-g samples. One untreated atherosclerotic monkey was used to determine the optimum tissue sample size. Five 1-g full-thickness myocardial samples were counted whole; divided into 10, 5, 4, 3, and 2 equal-weight samples; and then recounted. All counts are reported as counts per minute per gram of tissue. Counts among samples were similar (10 000 to 11 000 cpm/g). Counts in tissue samples divided into segments were greater than the whole (from 10% to 25% higher). There were no differences in total counts (no further increase) from myocardium divided into 0.2- or 0.1-g samples. Therefore, myocardial samples of 0.1 to 0.2 g were determined to be optimal because counts were maximized and internal quenching was minimized. Total time from euthanatization of the monkey to detection of chemiluminescence in the myocardial samples was very consistent between monkeys (approximately 20 minutes). There was minimal handling of the tissues during this time.
To confirm that myocardial samples had been ischemic, random samples of myocardium from adjacent sampling sites were incubated with a 30% solution of triphenyltetrazolium chloride. A brick-red color denoted nonischemic sections, and a tan color denoted ischemic sections of myocardium.
Detection of Superoxide Radicals
Chemiluminescence of
lucigenin was used to detect treatment
effects on superoxide production by tissues, as described
previously.11 17 The chemical specificity of this
light-yielding reaction for superoxide ion was reported
previously.18 In this study, sensitivity and specificity
of this assay were determined with xanthine (100 to 400 nmol/L) and
xanthine oxidase (0.002 U) to generate oxygen ions with or without
superoxide dismutase (SOD) (0.5 U/mL). These validation studies have
been described in detail.11 17 19
Combinations of xanthine
and xanthine oxidase produced transient chemiluminescence signals in a
manner dependent on the concentration of xanthine; these signals were
abolished by SOD.
Superoxide yields from xanthine–xanthine oxidase reactions were determined as described previously.20 Under the conditions of our assay, the yield of superoxide anion was found to be equal to 30% of the total xanthine present. This value was used to calibrate the lucigenin signal obtained during reactions with xanthine–xanthine oxidase. Total luminescence was quantified by integration of the areas under the curves generated in experiments. The correlation between chemiluminescence and superoxide anion generated with a simple fit was 0.99.
Chemiluminescence was detected by tissue samples after these samples were incubated in Krebs-HEPES buffer maintained at 37°C for 30 minutes. The tissue samples were then gently transferred to glass scintillation vials containing 0.25 mmol/L lucigenin that had been dark adapted.11 The samples were counted in a single-channel scintillation counter in the out-of-sequence mode. Counts were obtained at 2-minute intervals at room temperature. Vials containing lucigenin plus components (with the exception of tissue) were counted, and these blank values were subtracted from the chemiluminescence signals obtained from the tissue. Chemiluminescence was reported as nanomoles of oxygen anion per milligram dry wt per minute. Lucigenin-mediated chemiluminescence with segments of aorta also was measured in the presence of SOD (6 µmol/L) or after a 30-minute incubation with the hydroxyl radical scavenger mannitol (10 mmol/L) to evaluate the specificity of this reaction. Addition of mannitol abolished the chemiluminescence signal. The amount of time between preparation of the aortic tissue and completion of chemiluminescence assays was consistent (approximately 45 minutes). There was minimal handling of tissue during this time.
Determination of Extent of Atherosclerosis
Segments of
proximal and distal LAD were placed in 10% neutral
buffered formalin for determination of plaque size (measured as intimal
area).21 The artery segments were dehydrated in increasing
concentrations of ethanol, placed in paraffin blocks, and cut
longitudinally to the long axis of the artery. Histological sections
were stained with Verhoeff–van Gieson's stain and projected, and
the
cross-sectional area of the plaque lesion was measured with a
digitizer. The extent of atherosclerosis was expressed as the mean
cross-sectional area of intima in millimeters squared.
Statistical Analyses
Reported values are mean±SEM. To
determine the effect of
treatment on experimental end points (plasma lipids, blood pressure,
superoxide anion production, and plaque size), mean results were
compared by Student's t test. Simple correlations were used
to compare two lipid concentrations from the two laboratories or
correlations between chemiluminescence and superoxide anion generation.
The accepted level of significance was P<.05.
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Results |
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Blood Pressure, Plasma Lipids, and Extent of Atherosclerosis
Plasma concentrations of TPC, LDLC, and triglycerides were lower in monkeys fed fish oil than in those not fed fish oil (all P values <.05, Table 1
). Consumption of the
fish oil–containing diet increased the plasma concentration of 20- and
22-carbon -3 fatty acids, primarily at the expense of 18-carbon
fatty acids (P<.05, Table 2). There were no
differences between treatment groups in resulting mean arterial
pressures (75±6 mm Hg versus 78±8 mm Hg, P>.05).
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There were no differences in plaque extent between treatment groups in
the proximal or distal LAD (P>.05, Table 1
).
Atherosclerosis extent was smaller in the distal than proximal segments
of LAD in both treatment groups (P<.05, Table 1).
Superoxide Production
Superoxide anion concentrations in the
nonischemic myocardium were
similar between treatment groups of monkeys (P>.05, Fig
1). Dietary supplementation with fish oil prevented the
increase in superoxide anion production in the myocardium after
ischemia and reperfusion (P<.05, Fig 1). Fish oil
reduced
superoxide anion production in nonischemic coronary arteries
(P<.05, Fig 2). Fish oil abolished the
increase in superoxide anion production in coronary arteries after
ischemia and reperfusion (P<.05, Fig 2). Denudation
of
coronary arteries diminished the effects of fish oil on superoxide
anion production (P>.05, Fig 3). SOD applied
extracellularly inhibited the lucigenin signal by approximately
70%.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The three major findings of this study in nonhuman primates are that (1) supplementing the diet with fish oil resulted in increased plasma concentrations of
-3 fatty acids associated with reduced
superoxide anion production in the myocardium after ischemia and
reperfusion; (2) despite a lack of effect on plaque size, fish oil
reduced levels of superoxide anions in atherosclerotic coronary
arteries; and (3) fish oil prevented the increase in superoxide anion
production in atherosclerotic coronary arteries after ischemia and
reperfusion.
Effects of Fish Oil on Superoxide Anions
It is conceivable
that fish oil reduced superoxide anion
production in the myocardium and coronary arteries by separate
mechanisms. It has been proposed9 that invasion of
inflammatory cells into the ischemic myocardium and formation of oxygen
free radicals during reperfusion may promote cell death in the
myocardium. Inhibition of neutrophil infiltration into the ischemic
myocardium has been shown to reduce infarct size.22 Fish
oil has been reported to reduce prostaglandin and leukotriene
formation23 24 and decrease free oxygen radical
formation
by neutrophils.10 In our study, dietary supplementation
with fish oil increased the plasma concentrations of -3 fatty acids.
Therefore, -3 fatty acids may favorably modify the inflammatory
reaction in the myocardium and, through this mechanism, reduce
superoxide anion production in the myocardium after ischemia and
reperfusion.
This mechanism for inhibition of superoxide anion production by the myocardium may not apply to the coronary vasculature. Effects of fish oil on arterial superoxide anion production cannot be explained by effects on plaque size. However, there are numerous potential sources of superoxide anions in the wall of atherosclerotic coronary arteries that could be affected by fish oil. These include arachidonate metabolism, the cytochrome P450 system, electron transport, and xanthine dehydrogenase.11 Pagano et al25 reported recently that nicotinamide adenine dinucleotide phosphate oxidase is an important source of superoxide anion in the intima and adventitia of rabbit aorta. Additionally, superoxide anions may be produced by macrophages and other inflammatory cells in the intima and media of atherosclerotic arteries. Fish oil may have affected superoxide anion production by several of these mechanisms.
Denudation
of coronary arteries eliminated the superoxide
anion–inhibiting effects of fish oil, which suggests that fish oil
affected superoxide anion production primarily in the endothelium or
cells attached to the endothelium. This hypothesis is supported by
recent evidence that the fatty acids of fish oil incorporate into the
cell membrane phospholipids and cause competitive inhibition of
arachidonate metabolism.23 24 However, denudation may
have
removed underlying or adherent inflammatory cells along with
endothelial cells. Fisher et al10 noted that fish oil
reduces oxygen radical formation by polymorphonuclear leukocytes. Huth
et al26 recently reported that -3 fatty acids reduce
adhesion of monocytes and platelets that may be sources of superoxide
anion. Fish oil reduced plasma TPC and LDLC concentrations in monkeys
in the present experiment. It is possible that lowering plasma
concentrations of lipoproteins reduced the lipid composition,
particularly concentrations of oxidized LDL in the vessel wall, and
thereby improved endothelium-mediated vasodilation.
Implications
Ischemic damage to the myocardium is a major
concern during
cardiopulmonary bypass, coronary reperfusion in acute myocardial
infarction, thrombolytic therapy, and coronary angioplasty. One of the
major reasons that this study was done in atherosclerotic monkeys was
to model more closely the disease state of the arteries in patients
undergoing bypass and angioplasty procedures. Culp et al7
showed that dietary fish oil added to the diet for 4 to 6 weeks
resulted in smaller infarctions after coronary artery occlusion.
Similarly, Oskarsson et al6 reported that fish oil could
reduce myocardial infarction size after 90 minutes of coronary artery
occlusion followed by 6 hours of reperfusion. In both studies,
questions were raised about the potential mechanisms by which fish oil
limits damage to the myocardium after ischemia and reperfusion.
Although infarct size was not measured in the present experiment,
results indicate that suppression of superoxide anion production may
explain in part the protective effects of fish oil on myocardial damage
after reperfusion.
Results of recent studies in humans indicate that dietary supplementation with fish oil reduces the rate of restenosis after angioplasty.27 28 Active oxygen species have been shown to stimulate growth of vascular smooth muscle cells.29 Therefore, the inhibitory effects of fish oil on superoxide anion production may explain in part its beneficial effects on restenosis.
Reduction of superoxide anion production in atherosclerotic coronary arteries may have important implications in the pathogenesis of vasospasm and thrombosis. Nitric oxide is released by endothelial cells in response to various neurohumoral stimuli.30 Nitric oxide is rapidly inactivated by superoxide radical–generating systems31 and is protected by SOD.32 Nitric oxide has important protective actions in the vascular wall, including inhibition of smooth muscle contraction, smooth muscle proliferation, and platelet aggregation.30 Therefore, treatments that reduce superoxide anion production may reduce the risk of heart disease by promoting nitric oxide activity. Shimokawa et al8 showed that fish oil supplementation augments endothelium-mediated dilation of porcine coronary arteries, possibly through nitric oxide–mediated mechanisms. The results of the present experiment indicate that inhibition of vascular superoxide anion production may in part explain these effects.
Methodological Considerations
The monkeys were transported
from Indonesia to North Carolina in
the middle of the experiment. Transport is a stressful situation for
monkeys. Stress has been shown to be able to affect the extent of
atherosclerosis in coronary arteries.33 However, it is
unlikely that the stress of travel affected interpretation of the
present results because both groups of monkeys were stressed.
Additionally, we have shown that the effects of stress on endothelial
function of atherosclerotic coronary arteries are
transient.34
We used lucigenin to detect superoxide anion. The specificity of this technique was established previously.11 17 Lucigenin chemiluminescence is insensitive to hydroxyl radical, hydrogen peroxide, and nitric oxide. Additionally, the chemiluminescence of lucigenin has an advantage over other methods because it lends itself to measurements of superoxide production in intact vessels. By this method, it is not possible to determine whether superoxide dismutase production or scavenging is affected. A potential limitation of the present work is that the lucigenin signal produced by intact vessels is only 70% inhibited by SOD applied extracellularly. The explanation for this remains unclear but may relate to the fact that lucigenin produces chemiluminescence on the basis of both intracellular and extracellular superoxide anion. Therefore, SOD applied extracellularly may not completely inhibit the intracellular superoxide anion.
The percent of eicosapentaenoic acid in the fish oil diet was higher than that reported in other experiments.5 6 7 This is due, most likely, to the purified nature of the lemuru fish oil we used. Therefore, lemuru fish oil may be particularly useful in the prevention of myocardial damage after reperfusion.
Conclusions
The results of the present study indicate that
consumption of
a diet rich in fish oil inhibits production of superoxide anions in the
coronary arteries and myocardium of atherosclerotic monkeys. Reduction
in superoxide anion production may explain, in part, the reported
beneficial effects of fish oil on myocardial infarction size and
coronary artery vasomotion.
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Acknowledgments |
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This work was supported in part by grants PO1-RR-08562 (National Center for Research Resources) and PO1-HL-45666, R01-HL-48667, and RO1-HL-39006 (National Heart, Lung, and Blood Institute) from the National Institutes of Health, Bethesda, Md. The authors thank Jamie Fox and Yuichi Ohara for their expert assistance with the lucigenin assay and other experimental procedures and Karen Potvin Klein for editing this manuscript.
Received July 7, 1994; revision received August 31, 1994; accepted September 23, 1994.
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