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Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial ischemia-reperfusion (I/R) is a well-known
stimulus for acute inflammatory responses that promote cell death and impair pump function. Interleukin-10 (IL-10) is an endogenous, potent
anti-inflammatory cytokine. Recently, it has been proposed that IL-10
inhibits inducible nitric oxide synthase (iNOS) activity after
myocardial I/R and consequently exerts cardioprotective effects.
However, whether this actually occurs remains unclear. To test this
hypothesis, we utilized iNOS-deficient (
/), IL-10 /, and
IL-10/iNOS / mice to examine the potential mechanism of
IL-10-mediated cardioprotection after myocardial I/R. Wild-type, iNOS
/, IL-10 /, and IL-10/iNOS / mice were subjected to in vivo myocardial ischemia (30 min) and reperfusion (24 h).
Deficiency of iNOS alone did not significantly alter the extent of
myocardial necrosis compared with wild-type mice. We found that
deficiency of IL-10 resulted in a significantly (P < 0.05) larger infarct size than that in wild-type hearts. Interestingly,
deficiency of both IL-10 and iNOS yielded significantly
(P < 0.01) larger myocardial infarct sizes compared
with wild-type animals. Histological examination of myocardial tissue
samples revealed augmented neutrophil infiltration into the I/R
myocardium of IL-10 / and IL-10/iNOS / mice compared with
hearts of wild-type mice. These results demonstrate that 1)
deficiency of endogenous IL-10 exacerbates myocardial injury after I/R;
2) the cardioprotective effects of IL-10 are not dependent
on the presence or absence of iNOS; and 3) deficiency of
IL-10 enhances the infiltration of neutrophils into the myocardium
after I/R.
cytokines; nitric oxide; ischemia; myocardial injury; mouse
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INTERLEUKIN-10
(IL-10) is an important anti-inflammatory cytokine that attenuates the
severity of various disease states. Consequently, many investigators
have addressed the possible protective role of IL-10 in multiple
pathological models. Lentsch et al. (19) demonstrated that
IL-10 administration diminished pulmonary inflammatory cell
infiltration in rats. In addition, recent studies (22, 24)
suggest that IL-10 may impede the development of atherosclerosis. IL-10
therapy may also inhibit intimal hyperplasia after vascular injury in
hypercholesterolemic subjects (2). Much of the interest in
IL-10 arose from the generation of mice deficient (/) in the IL-10
gene and their development of colitis (14). Subsequent
work in IL-10 / mice demonstrated a vital role for IL-10 in
attenuating cardiac allograft rejection (26) and
lipopolysaccharide (LPS)-induced vascular dysfunction (5). These findings and others fuel further investigation into the potential
mechanisms of IL-10-mediated cytoprotection.
Unlike IL-10, the role of inducible nitric oxide (NO) synthase (iNOS)
in inflammation is highly controversial. Many studies have implicated
iNOS as a pathogenic mediator in renal ischemia-reperfusion (I/R) injury (20) and shock states (30).
Others have found iNOS to be protective in the setting of allograft
arteriosclerosis (28) and ischemic preconditioning
(31). Although the role of iNOS in myocardial I/R injury
is unclear, recent studies have investigated its role. Using isolated,
perfused iNOS / mouse hearts, Xi et al. (36) did not
demonstrate a role for iNOS in myocardial I/R injury. Conversely,
another study (35) demonstrated an injurious role for iNOS
using an iNOS inhibitor.
Recently, interest in the role of IL-10 in the development of injury
after myocardial I/R has grown. It has previously been demonstrated
that exogenous administration of IL-10 attenuates the extent of
polymorphonuclear neutrophil (PMN) infiltration and I/R injury in rats
(6). Recently, Yang et al. (37) demonstrated that endogenously produced IL-10 is critical in diminishing myocardial injury after myocardial I/R. The authors of this recent study (37) suggest that endogenous IL-10 inhibits the activity
of iNOS after myocardial I/R. Accordingly, IL-10 deficiency might augment the production of iNOS-derived NO and possibly form potent oxidants such as peroxynitrite (ONOO
). In fact, other
studies of the protective effects of IL-10 directly or indirectly
implicated iNOS as a pathogenic mediator of the injury/dysfunction in
IL-10 / mice (5, 23, 26).
This study was designed to answer the following questions:
1) Does deficiency of IL-10 promote myocardial injury after
myocardial I/R? 2) Is the cardioprotective mechanism of
IL-10 mediated by inhibition of iNOS? We attempted to definitively
answer these questions through the use of IL-10 / and iNOS/IL-10
/ mice in an in vivo model of left anterior descending (LAD)
coronary artery occlusion and reperfusion.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Transgenic mice.
IL-10 / (14), iNOS / (15), and
IL-10/iNOS / mice were generated using homologous recombination.
Male, age-matched, mutant, and littermate wild-type mice were used in
this study. All experimental procedures complied with the National
Institutes of Health Guide for the Care and Use of Laboratory
Animals approved by the Council of the American Physiological
Society and with federal and state regulations. All experimental
procedures were approved by the Louisiana State University Health
Sciences Center Animal Care and Use Committee.
Surgical procedures.
Wild-type (n = 15), iNOS / (n = 9),
IL-10 / (n = 9), and IL-10/iNOS /
(n = 7) mice were allowed free access to standard rodent chow, exposed to 12:12-h light-dark cycles, and housed in a
climate-controlled room. The surgical protocol and infarct size
determination were performed similar to methods described previously
(8, 11). Briefly, the mice were anesthetized with pentobarbital sodium (50 mg/kg ip) and ketamine (50 mg/kg ip). Through
direct visualization, the mice were orally intubated with polyethylene-90 tubing. Body temperature was maintained between 36 and
37°C by using a rectal thermometer and infrared heating lamp. The
animals were then connected to a rodent ventilator (model 683, Harvard
Apparatus). After a median sternotomy was performed, the LAD coronary
artery was visualized and ligated with a 7-0 silk suture.
Ischemia was confirmed by pallor and hypokinesis distal to the
occlusion. After 30-min LAD coronary artery occlusion, the ligature was
removed and reperfusion was confirmed visually. The chest wall was
closed with three interrupted sutures (4-0 silk), and the skin was
approximated with a continuous suture (4-0 silk). The animals were
given butorphanol tartrate (~0.1 mg/kg sc) for analgesia. The mice
were given supplemental oxygen via a nasal cone and allowed to recover
in a temperature-controlled area.
Assessment of myocardial PMN infiltration.
Routine histological staining was performed on multiple sections of
midventricular cardiac sections to determine the extent of PMN
infiltration. Wild-type (n = 8), iNOS /
(n = 4), IL-10 / (n = 4), and
IL-10/iNOS / (n = 4) mice were subjected to 30 min
of LAD coronary artery occlusion and 24-h reperfusion as described
above. Midventricular tissue slices (1 mm thick) were prepared from
hearts subjected to the myocardial I/R protocol after the completion of
all experimental procedures. The tissue sections were immediately fixed
and stored in a 10% neutral buffered formalin solution (Sigma). The
tissue slices were then embedded in paraffin, cut into 10-µm
sections, and placed on slides. The tissue specimens were then stained
with Gill no. 3 hematoxylin and eosin. The slides were then viewed
microscopically, and the number of PMNs per millimeter squared was
determined. For each of the hearts examined, the number of PMNs was
counted in six fields of three independent tissue sections by an
observer blinded to the experiment.
Statistical analyses. All data were subjected to ANOVA with Scheffé's post hoc test. All values are reported as means ± SE. Statistical significance was set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocardial infarct size determination.
Wild-type (n = 15), iNOS / (n = 9),
IL-10 / (n = 9), and IL-10/iNOS /
(n = 7) mice were subjected to 30 min of in vivo, regional coronary ischemia and 24 h reperfusion. The
area-at-risk (AAR) per left ventricle (AAR/LV) for infarction was
identified using in vivo Evans blue injection. All groups of mice were
subjected to similar AAR (P value not significant). The
percentage of infarction per AAR (Inf/AAR) in wild-type hearts was
37 ± 4% (Fig. 1). Deficiency of
iNOS did not significantly affect the degree of myocardial necrosis (48 ± 4%). However, IL-10 / hearts (60 ± 6%)
suffered ~90% more necrosis than wild-type hearts (P < 0.01). In addition, deficiency of both IL-10 and iNOS (65 ± 6%) resulted in ~120% more necrosis than wild-type hearts
(P < 0.01). When expressed as area of Inf/LV, a
similar pattern was also observed.
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Myocardial histology.
PMN infiltration was assessed by routine histological examination of
midventricular slices after in vivo I/R (Fig.
2). Wild-type hearts exhibited 58 ± 2 PMNs/mm2. Deficiency of iNOS (62 ± 4 PMNs/mm2) did not significantly alter PMN infiltration
compared with wild-type hearts. However, IL-10 deficiency (92 ± 2 PMNs/mm2) resulted in ~60% more PMNs compared with
wild-type hearts (P < 0.01). Furthermore, deficiency
of both IL-10 and iNOS (100 ± 4 PMNs/mm2) resulted in
72% more PMNs than wild-type hearts (P < 0.01).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study answers two important questions: 1) Is
endogenous IL-10 cardioprotective in the setting of myocardial I/R?
2) Are the cardioprotective effects of endogenous IL-10
mediated by inhibition of iNOS? In this study, we have shown that
deficiency of endogenous IL-10 augments PMN infiltration and
exacerbates myocardial I/R injury. To answer the pressing question of
the mechanism of IL-10-mediated cardioprotection we examined the
possible role of iNOS, as suggested previously (37). The
present study clearly demonstrates that inability to upregulate iNOS
(in the absence or presence of IL-10) does not protect the I/R
myocardium from necrosis. Furthermore, the elevated infarct size was
not due to increased myocardial oxygen demand during ischemia
(Table 1).
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IL-10 is a potent anti-inflammatory cytokine. Prior studies of IL-10
have demonstrated a protective role in a variety of pathological states
including colitis (14), hepatic I/R (38),
atherosclerosis (22, 24), allograft rejection
(26), leukocyte-endothelial cell interactions
(7), and myocardial I/R (6, 37). In the
present study, we confirmed the cardioprotective actions of IL-10 after
in vivo myocardial I/R. Furthermore, we demonstrated significant
augmentation of PMN infiltration into the I/R myocardium. It is
important to note that the reperfusion period in the present study was
significantly longer than that in a previous study (37) of
IL-10 / mice. Another difference between these studies is the need
for donor blood in the previous study (37), whereas we did
not utilize blood transfusions in the present study.
Endothelial cell-derived NO exhibits a multitude of physiological
functions. NO promotes vasodilation, inhibits smooth muscle cell
proliferation (3), impairs platelet aggregation
(25), attenuates leukocyte-endothelial cell interactions
(13, 16), decreases microvascular
permeability(12), and diminishes myocardial I/R injury
(9). Although the role of endothelial-derived NO appears
to be cardioprotective, the role of iNOS-derived NO is unclear. In the
present study, deficiency of iNOS did not significantly affect the
extent of myocardial necrosis. Similarly, a previous ex vivo study of
myocardial I/R injury in iNOS / mice (36) demonstrated
no role for iNOS in the development of myocardial I/R injury. Contrary
to this report, other studies (32, 35) using an iNOS
inhibitor after myocardial I/R found iNOS to be injurious. The role of
iNOS in myocardial I/R injury will continue to be highly controversial.
One of the primary arguments for an injurious role of iNOS after
myocardial I/R is the hypothetical formation of ONOO.
ONOO is formed from approximately equimolar
concentrations of NO and superoxide (4). It has previously
been reported to be formed and promote injury after myocardial
ischemia in isolated rat hearts (21, 33).
However, evidence for the formation of ONOO in vivo is
often indirect at best. Although tyrosine can be
nitrosylated after the formation of ONOO, it is in not a
specific marker for ONOO formation (4,
27). Even if ONOO were formed in vivo, it is not
likely to be injurious in light of a previous report that
demonstrated protective effects of ONOO administered
during in vivo myocardial I/R (17).
The present study demonstrates elevated PMN infiltration in IL-10 /
and IL-10/iNOS / hearts after regional myocardial I/R. The role of
PMNs in myocardial I/R injury has received much attention (1, 10,
18, 29, 34). The mechanism of neutrophil recruitment into an
area of inflammation occurs via the interaction between leukocyte
adhesion molecules and endothelial adhesion molecules. Transmigration
of activated PMNs into the I/R myocardium can further damage
cardiac tissue. Consequently, demonstration of enhanced PMN
infiltration in IL-10 / and IL-10/iNOS / mice may partially
address the mechanism of augmented myocardial injury in these hearts.
However, the proximal signal responsible for this injurious cascade is
not known.
Future studies could address the role of IL-10 in possible alterations in contractile performance after myocardial I/R. Our present findings indicate that endogenous IL-10 is important in attenuating the extent of PMN infiltration and myocardial injury after I/R. Furthermore, we clearly demonstrate that deficiency of IL-10 does not exacerbate myocardial injury via iNOS.
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ACKNOWLEDGEMENTS |
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Willis-Knighton Medical Center (Shreveport, LA) and DeRoyal Surgical (Powell, TN) generously donated surgical supplies.
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FOOTNOTES |
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This research was supported by National Heart, Lung, and Blood Institute Grants RO1-HL-60849 and PO1-DK-43785 to D. J. Lefer.
Address for reprint requests and other correspondence: D. J. Lefer, Dept. of Molecular and Cellular Physiology, Louisiana State Univ. Health Sciences Center, 1501 Kings Highway, Shreveport, Louisiana 71130 (E-mail: dlefer{at}lsuhsc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 18 October 2000; accepted in final form 26 February 2001.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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 E. Gross, K. Hawkins, A. Pushkin, P. Sassani, R. Dukkipati, N. Abuladze, U. Hopfer, and I. Kurtz Phosphorylation of Ser982 in the sodium bicarbonate cotransporter kNBC1 shifts the HCO3- : Na+ stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells J. Physiol., December 12, 2001; 537(3): 659 - 665. [Abstract] [Full Text] [PDF]
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