(Circulation. 1999;99:2157-2163.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Essential Role of Inducible Nitric Oxide Synthase in Monophosphoryl Lipid A–Induced Late Cardioprotection
Evidence From Pharmacological Inhibition and Gene Knockout Mice
From the Division of Cardiology, Medical College of Virginia, Virginia Commonwealth University, Richmond.
Correspondence to Dr Rakesh C. Kukreja, Eric Lipman Professor, Division of Cardiology, Box 980281, Medical College of Virginia, Richmond, VA 23298. E-mail rakesh{at}hsc.vcu.edu
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Abstract |
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Background—Monophosphoryl lipid A (MLA), a nontoxic analogue of endotoxin, is a pharmacological agent that is known to have anti-ischemic effects. Mechanisms involved with the cardioprotection are still unclear. A role for inducible nitric oxide synthase (iNOS) was recently proposed. We tested this hypothesis using S-methylisothiourea (SMT), one of the specific pharmacological inhibitors of iNOS, as well as iNOS gene knockout mice.
Methods and Results—Adult male ICR or B6,129 mice were pretreated with either MLA 35 or 350 µg/kg IP (MLA35 or MLA350) or vehicle 24 hours before global ischemia/reperfusion, which was carried out in a Langendorff isolated perfused heart model (n=8 to 9 per group). Another group of MLA350 mice received SMT 3 mg/kg IP 30 minutes before heart perfusion. Ventricular contractile function and heart rate were not different between the groups during the preischemia and reperfusion periods (P>0.05). Preischemic basal coronary flow was significantly increased in all MLA350 but not MLA35 mice. Myocardial infarct size was reduced significantly, from 26.9±2.9% of risk area in vehicle-treated mice to 13.5±2.4% in the MLA350 group (mean±SEM, P<0.05). This reduction in infarct size was accompanied by augmented nitrite/nitrate accumulation, from 0.23±0.05 nmol/mg protein in the vehicle group to 0.97±0.27 nmol/mg protein in MLA350 mice (P<0.01). Infarct size increased significantly, to 22.2±2.8% after treatment with SMT in the MLA350 group. Furthermore, MLA350 failed to reduce infarct size in iNOS knockout mice (25.5±3.6%).
Conclusions—These results demonstrate a direct association of infarct size reduction with increased NO production with MLA350. An obligatory role for iNOS in mediating the cardioprotective effect induced by MLA was confirmed with the pharmacological inhibition and gene knockout mice.
Key Words: ischemia • reperfusion • myocardial infarction • pharmacology • nitric oxide
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Introduction |
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Protection of the ischemic heart has been the subject of experimental and clinical research for more than 2 decades. A number of protection strategies have been developed, including the pharmacological approaches.1 2 The phenomenon called "preconditioning," with its potent ability to enhance cellular endogenous mechanisms against ischemia/reperfusion injury, has been extensively investigated by many investigators. Identification of novel pharmacological agents that can potentially induce long-lasting protection against ischemia and reperfusion injury is currently a major area of investigation. Among the several agents that can potentially precondition myocardium against ischemia, monophosphoryl lipid A (MLA) has been well investigated and is thought to be promising for future clinical applications in humans.3
MLA is an analogue of endotoxin, which was derived and purified from bacterial lipopolysaccharide in the 1980s.3 It retains several of the immunomodulatory properties of the parent endotoxin molecule without the associated toxicity. MLA appears to maintain many of the beneficial immunological activities of the parent molecule, including induction of tolerance to endotoxemia in both laboratory animals4 5 and human subjects.6 These beneficial effects of MLA may be achieved via its ability to induce cytokines, macrophage activation, and colony-stimulating factor induction with much less toxic effects than are associated with the parent endotoxin.5 7 8 9 To date, this less toxic and less pyrogenic agent has been investigated primarily for use as an immunotherapeutic,10 immunoprophylactic,11 or adjuvant for vaccines.12 Studies have shown that MLA also has cardioprotective effects when administered 24 hours before ischemia/reperfusion in rats,13 14 rabbits,2 15 16 dogs,17 18 and cultured adult rat cardiac myocytes.19
The mechanism of MLA-induced protection is not well understood, although several possibilities have been suggested. It was shown that lipopolysaccharide pretreatment induces heat shock protein 70i expression in rat myocardium that is associated with the delayed cardioprotection.20 However, MLA failed to induce a similar induction of this protein in rabbit heart.2 15 More recently, Zhao et al16 demonstrated that delayed cardioprotection with MLA can be abolished by aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS). Unfortunately, pharmacological inhibitors do not always give satisfactory answers because many of these agents are not highly specific and do not entirely inhibit the target enzyme. Because NO is produced from L-arginine through a chemical reaction that is catalyzed by at least 3 major isoforms of NOS, ie, iNOS (inducible), eNOS (endothelial), and nNOS (neuronal),21 there is an unavoidable redundancy in functional actions among the different NOS isoforms. Therefore, the exact role of iNOS in MLA-induced cardioprotection requires further direct confirmation with more specific methods, such as state-of-the-art gene knockout technology. The iNOS gene knockout mice that were recently developed22 provide us an excellent opportunity to study the role of iNOS in the mechanisms of MLA-induced cardioprotection. The present study in a murine model focused on the following 3 specific aims: (1) to demonstrate that MLA induces delayed cardioprotection in the mouse heart, (2) to determine that MLA-induced cardioprotection is mediated by NO, and (3) to confirm that an intact iNOS system is obligatory for the MLA-induced cardioprotection.
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Methods |
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Animals
Adult male outbred ICR mice were supplied by Harlan Sprague Dawley Co (Indianapolis, Ind), and the adult male iNOS gene knockout B6,129 mice were purchased from Jackson Laboratory (Bar Harbor, Me). The iNOS knockout mice were generated according to Laubach et al.22 In brief, to generate chimeric mice, C57BL/6J (B6) blastocysts were injected with the recombinant 129-derived ES cells and implanted into pseudopregnant females for development. Chimeric males were then mated with B6 females, and the resulting B6,129 F1 heterozygote mutant (+/-) mice were interbred to generate F2 homozygous mutant (-/-) mice for the iNOS disruption. Their progeny were genotyped by Southern analysis. The iNOS knockout mice were indistinguishable from wild-type mice in appearance, growth rate, reproduction, and histology.
Drugs
MLA and its vehicle solvent were provided by Ribi ImmunoChem
Research Inc. The vehicle was composed of 40% propylene glycol and
10% ethyl alcohol in water. Mice were treated
intraperitoneally with either MLA 35 or 350 µg/kg
or volume-matched vehicle. S-Methylthiourea sulfate (SMT), a
selective inhibitor of iNOS,23 was
purchased from Sigma Chemical Co.
Langendorff-Perfused Isolated Heart Preparation
The methodology of isolated perfused mouse heart was described
in detail previously.24 25
Ischemia/Reperfusion Protocol
After a 30-minute stabilization period, hearts were subjected to
20 minutes of no-flow normothermic global ischemia
and 30 minutes of reperfusion. The 7 experimental groups involved in
this study are shown in Figure 1
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Exclusion Criteria
Hearts were excluded from further data analysis as a
result of one of the following undesirable situations: (1) time delay
in the aortic cannulation (>3 minutes), (2) damage of aorta during the
cannulation, (3) sustained arrhythmia during the 30 minutes of
stabilization, and (4) depressed ventricular developed
force (<0.1 g) at the end of stabilization.
Measurement of Infarct Size
At the end of the experiment, hearts were immediately removed
from the Langendorff apparatus, weighed, and frozen at
–20°C. The frozen heart was then cut manually into 7 or 8 transverse
slices of approximately equal thickness (
0.8 mm) and stained by
incubation in 10% triphenyl tetrazolium chloride (TTC) for 30 minutes.
TTC buffer was then replaced by 10% formaldehyde, and the slices were
fixed for 4 to 6 hours before measurement of the infarct area and the
risk zone by computer morphometry (Bioquant System IV). The risk area
was the sum of total ventricular area minus cavities. The
infarct size was calculated as percent of risk area.
Measurement of NO Products
Thirty-six ICR mice were pretreated with vehicle or MLA 35 or
350 µg/kg IP. Twenty-four hours later, hearts were isolated and
subjected to either 5 minutes of aerobic perfusion (37°C) for washing
out the blood (ie, nonischemic hearts) or
ischemia/reperfusion as described above (n=6 each). The
ventricular tissue was immediately collected, frozen, and
stored at –80°C. For preparation of tissue extracts, 2 mL of
ice-cold homogenization buffer (0.1 mmol/L
phosphate buffer, pH 7.4) was added to the powdered tissue sample, and
the mixture was homogenized in a Polytron equipped with a
PT10 probe. The homogenate was then spun in a
microcentrifuge for 10 minutes, and the supernatant
(representing the cytosol) was transferred to a fresh tube
and kept frozen at –80°C until analyzed. Protein
concentration was determined with a BIO-RAD protein assay kit. Total NO
oxidation products were measured with a SIEVERS nitric oxide
analyzer (model 280NOA). NO undergoes a series of reactions
with several molecules present in biological fluids, leading to the
accumulation of the final products, nitrite and nitrate. Thus, the
index of total NO production is the sum of both nitrite and
nitrate accumulated in the tissue samples. The reducing agent used for
the analysis was a saturated solution of vanadium (III)
chloride (VCl3) in 1 mol/L HCl. To minimize
foaming from the heart tissue samples containing protein, 100 µL of a
1:30 dilution of Dow Corning Antifoam C was added to the
VCl3 reagent. Five milliliters of the reagent was
used in the purge vessel for analysis of 30 to 50 samples. At a
temperature of 90°C, VCl3 reagent
quantitatively converts nitrite, nitrate, and S-nitroso
compounds to NO, which is then measured by the NO analyzer.
Data Analysis and Statistics
Each experimental group consisted of 8 or 9 animals. The group
means and their SEMs for each parameter are
presented. One-way ANOVA was used to compare the values of 
3
groups. If a significant value of F was obtained, the
Student-Newman-Keuls post hoc test was subsequently used to make
pairwise comparisons among the groups. Paired t test was
also used to compare any pretreatment and posttreatment values for any
given parameter. A value of P<0.05 was
considered statistically significant
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Results |
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Exclusions
A total of 78 hearts were subjected to the ischemia/reperfusion protocol (Figure 1
) in the 7
experimental groups (n=8 to 9 each) for the assessment of
ventricular function as well as infarct size. Among them,
16 hearts (ie, 21% of the 78 perfused hearts) were excluded according
to the exclusion criteria described under Methods. An additional 36
hearts were used for measurement of nitrite levels in the myocardial
tissue extracts.
Baseline Cardiac Hemodynamics and Contractile
Function
Morphometric characteristics of the mice as well as the
preischemic baseline values are summarized in the
Table. There was no significant
difference in the preischemic basal value of heart rate and
ventricular contractile parameters (ie,
developed force, rate-force product, and resting tension) between
the groups, although pretreatment with high-dose MLA exhibited a
positive inotropic effect during the first 20 minutes of stabilization
(Figure 2). This effect on myocardial
contractility persisted in the SMT-treated group but
was absent in the iNOS knockout group. The coronary flow rate
was significantly increased in all MLA350-treated groups compared with
the vehicle group (P<0.05, Figure 4).
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Postischemic Cardiac Hemodynamic and
Contractile Function
After 20 minutes of global ischemia,
ventricular developed force and rate-force product were
significantly depressed in all experimental groups, regardless of the
pretreatment conditions during reperfusion (Figure 2). The
resting tension and heart rate were not significantly different between
the preischemic and reperfusion periods (Figure 3). Postischemic
coronary flow was not significantly different from its
preischemic values for all the groups (P>0.05;
Figure 4). The average coronary
flow rate was generally higher in MLA-treated groups than in the
vehicle group, although these differences were not significant
(P>0.05).
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Infarct Size
Myocardial infarction was evident in the mouse hearts after
ischemia/reperfusion. Pretreatment with MLA reduced the infarct
size in a dose-dependent manner (Figure 5A). The high-dose MLA (ie, 350 µg/kg)
caused a significant reduction in infarct size, to 13.5±2.4% of risk
zone compared with 26.9±2.9% in the vehicle-treated group
(P<0.05). The MLA-induced reduction in infarct size was
abolished by pretreatment with SMT (22.2±2.8%) and was completely
absent in the iNOS knockout mice (25.5±3.6%). The area at risk for
the globally ischemic hearts was not different between the
groups (Figure 5B). Representative samples of
the TTC-stained heart slices are shown in Figure 6. The viable (area in red color) and
necrotic (area in pale color) tissues were clearly distinguishable in
these pictures.
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Myocardial Nitrite/Nitrate Content
Pretreatment with MLA caused a moderate but statistically
insignificant decrease of myocardial nitrite/nitrate in the
nonischemic hearts 24 hours later. The nitrite/nitrate levels
increased significantly only in the high-dose MLA-treated mice after
ischemia/reperfusion (0.97±0.27 nmol/mg protein) compared with
the vehicle group (0.23±0.05; P<0.01; Figure 7). The postischemic
myocardial accumulation of nitrite/nitrate was associated with the
reduction in infarct size with MLA (Figure 5).
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Discussion |
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Novel Findings
The salient findings of this study are summarized as follows. (1) Higher doses of MLA (ie, 350 µg/kg), when administered 24 hours before ischemia/reperfusion, resulted in a significant reduction of myocardial infarct size and improvement in coronary flow. The antinecrotic effect was not associated with improvement in the postischemic ventricular contractile function. (2) The cardioprotective effect was abolished by SMT, a specific inhibitor of iNOS, and was completely absent in iNOS knockout mice. (3) The cardioprotective dose of MLA resulted in a significant increase in nitrite/nitrate accumulation in the ischemic/reperfused heart. Taken together, our results suggest that high-dose MLA induces a significant anti-ischemic protection in the mouse heart, which was associated with increased accumulation of NO products. These data, coupled with a lack of protection in iNOS knockout mice and blockade of cardioprotection with iNOS inhibitor in normal mice, strongly suggest a cause-and-effect relationship of NO in the pharmacological protection induced by MLA. To the best of our knowledge, this is the first study to establish a direct role of NO in delayed pharmacological preconditioning in the ischemic mouse heart.
Anti-Ischemic Effects of MLA in Heart
MLA has been shown to induce such immunostimulatory effects as
cytokine production, macrophage stimulation,
and a variety of other effects on both humoral and cell-mediated immune
response.5 7 8 9 In vivo studies demonstrated the ability
of MLA to protect the heart during
ischemia/reperfusion.2 15 16 17 The present
study clearly demonstrates a dose-dependent antinecrotic effect of MLA
(Figure 5). The lower dose of MLA (35 µg/kg) did not reduce
infarct size. This finding is in accordance with a previous
report15 in which a similar dose of MLA reduced
postischemic infarct size in the in situ rabbit heart after
regional ischemia but not in the isolated heart subjected to
global ischemia. In addition, it seems that rodents require a
much higher drug concentration to exert the cardioprotective effects.
Tosaki et al14 reported significant antiarrhythmic effects
of MLA with 300 and 450 µg/kg MLA in the isolated working rat heart.
Similar species-related differences in induction of late
cardioprotection were observed in the mouse heart,25 in
which whole-body heat shock failed to induce anti-ischemic
effects. However, MLA-induced infarct size reduction was comparable to
"acute" ischemic preconditioning in the isolated mouse
heart.24
NO and Delayed Cardioprotection
NO is an essential modulator of biological systems,
including the cardiovascular system.21 It
is critical in the signal transduction of ischemic
myocardium.26 Numerous studies have shown the
beneficial and harmful effects of NO in the
physiological regulation and control of the
cardiovascular system. On one hand, NO is a free
radical itself and can also form peroxynitrite, a more potent oxidant
that can potentially cause cellular membrane lipid peroxidation, which
may lead to myocardial dysfunction.27 28 29 30 In contrast, NO
is the modulator of vascular smooth muscle tone, and its biological
action can be cardioprotective against ischemia/reperfusion
injury through coronary vasodilatation and reduction in
myocardial oxygen consumption via upregulation of cGMP.31
Pretreatment with NO donors has been reported to be beneficial in the
ischemic myocardium. Both antiarrhythmic and
anti-infarction32 effects of the NO donors have been well
documented. More recently, NO has been appreciated as the possible key
trigger and mediator for ischemic
preconditioning.33
NO may enhance myocardial protection by cGMP-dependent as well as
cGMP-independent mechanisms (Figure 8).
NO is a unique messenger because it is produced in one cell and
diffuses into adjacent target cells to activate cytosolic
guanylate cyclase–bound heme to generate the NO-heme
adduct of guanylate cyclase.26 NO may also
modulate KATP channels via the second messenger
cGMP. The cGMP-dependent protein kinases may be capable of
phosphorylating KATP channels and priming the
channel to offer cardioprotection.34 Cameron et
al35 provided direct evidence that NO enhances
KATP channel activity in hypertrophied
ventricular myocytes. Opening of the
KATP channel appears to be protective because of
the increase in outward potassium current, resulting in shortening of
the action potential, which in turn may spare ATP, thereby allowing
less entry of calcium into the myocyte through the voltage-sensitive
calcium channel.36 Decreased intracellular calcium
overload may reduce ischemic injury and lead to better myocyte
preservation. There is mounting evidence supporting the involvement of
KATP channels in the mechanism of
ischemic preconditioning36 37 and pharmacological
protection with MLA.38 39 40
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iNOS and Delayed Cardioprotection
Three major isoforms of NOS, ie, iNOS, eNOS, and nNOS, are able to
catalyze the chemical reaction that produces NO from
L-arginine. eNOS and nNOS are constitutively expressed in
normal biological systems and are important mediators of cellular
signal transduction. iNOS is expressed under such
pathophysiological conditions as endotoxin
challenge and stress and is capable of producing large amounts of NO,
which tends to be cytotoxic.28 However, it has been
increasingly recognized that iNOS can be very important in the immune
reaction against microbacterial and environmental insults. In the
present investigation, we observed complete lack of MLA-induced
protection in the iNOS knockout mice, suggesting an obligatory role of
this isoform in the protective process. Furthermore, the
cardioprotection was significantly abolished by SMT, which was reported
to be 10- to 30-fold more potent as an inhibitor of iNOS
than the L-arginine analogues, as well as
aminoguanidine.23 Therefore, the abrogation of MLA-induced
anti-ischemic effect could be at least in part due to the
inhibition of iNOS in the ischemic heart. The cardioprotective
dose of MLA significantly increased NO production after
ischemia/reperfusion but not in the nonischemic hearts,
suggesting that iNOS was functional only in the ischemic
hearts. Similarly, Zhao et al16 observed that no increase
of iNOS enzyme activity occurred in the nonischemic heart
tissue in MLA-treated rabbits. This suggests that posttranslational
modifications of the iNOS enzyme are required before it is capable of
generating NO. It is possible that ischemia may
activate certain kinases (such as protein kinase C and tyrosine
kinase) or inhibit phosphatases that may promote
phosphorylation-dependent activation of the inactive
iNOS induced by MLA.
The role of constitutive forms of NOS in MLA-induced protection is
still not clear. We observed a consistent improvement in
preischemic coronary flow in all MLA-treated groups
(Figure 4). Blocking iNOS with SMT did not reverse the
improvement of coronary flow in MLA-treated mice. Also, SMT
only partially (although significantly) blocked the antinecrotic effect
of MLA (Figure 5). These data suggest that MLA may have
stimulated eNOS in the heart and that the drug may be improving
vascular endothelial function independently of the iNOS
enzyme. Future studies in eNOS knockout mice will provide insights on
the role of eNOS in MLA-induced cardioprotection.
Conclusions and Future Directions
We have shown that MLA induces a dose-dependent cardioprotection
against myocardial infarction in the ischemic mouse heart. This
antinecrotic effect was associated with enhanced accumulation of
nitrite/nitrate in the ischemic tissue, was blocked by
selective inhibition of iNOS, and was completely absent in iNOS
knockout mice. To the best of our knowledge, this is the first direct
evidence supporting an obligatory role of iNOS in mediating the delayed
cardioprotection by MLA. Further investigations in the murine model are
necessary to elucidate (1) the potential role of eNOS or nNOS in
MLA-induced cardioprotection, (2) the key type(s) of cytokines
and their receptors that may be responsible in activation of iNOS, and
(3) other pharmacological agents that could induce late preconditioning
via signal transduction pathways similar to those of MLA.
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Acknowledgments |
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This work was funded in part by grants from the NHLBI (HL-51045, HL-59469) to Dr Kukreja. Dr Xi was supported by a NRSA fellowship from the NIH (HL-07537) and a Research Fellowship from the American Heart Association, Mid-Atlantic Affiliate (F98273V). We thank Dr R. Hutte of Sievers Instruments, Inc, for his help in measuring tissue nitrite/nitrate concentrations and Dr G.T. Elliott of Ribi ImmunoChem Research Inc for providing MLA.
Received September 7, 1998; revision received November 20, 1998; accepted December 17, 1998.
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