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B induction during in vivo hypoxia in dorsocaudal brain stem
of rat: effect of MK-801 and
L-NAME
Constance S. Kaufman Pediatric Pulmonary Research Laboratory, Departments of Pediatrics and Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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In the
nucleus of the solitary tract, NMDA receptors are critical for the
hypoxic ventilatory response while neuronal nitric oxide synthase (NOS)
modulates the late component of this response. Nuclear factor (NF)-
B
is a ubiquitous transcription factor that increases the expression of
multiple stress-activated genes. We sought to examine temporal changes
in expression of NF-B within the dorsocaudal brain stem of conscious
rats after exposures to 10% O2.
Time-dependent increases in NF-B occurred with hypoxia and peaked at
60 min. Pretreatment with the
N-methyl-D-aspartate (NMDA)-receptor channel antagonist dizocilpine maleate (MK-801) markedly attenuated NF-B complexes during hypoxia. In contrast, after NOS inhibition with
NG-nitro-L-arginine methyl
ester (L-NAME),
although NF-B was diminished in normoxia, increased NF-B
expression still occurred with hypoxia. Increased phosphorylation of
the NF-B regulatory unit [inhibitory (I)B] was
detected by immunoblotting and also peaked at 60 min. Phosphorylation
of I-B during hypoxia was attenuated by MK-801 but not by
L-NAME. Thus NMDA-receptor
activation in the dorsocaudal brain stem during hypoxia elicits in
NF-B activity marked enhancements that are unaffected after NOS
blockade.
nuclear factor-B; NG-nitro-L-arginine methyl ester; hypoxia; transcription factors; nitric oxide; glutamate; N-methyl-D-aspartate
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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NUCLEAR FACTOR-B (NF-B) is
a family of hetero- or homodimer proteins with DNA-binding
and transcription-activation capacities that is ubiquitously involved
in the regulation of various stress-related genes. NF-B activation
is an early inducible event that does not require de novo protein
synthesis (2). Inactive NF-B is located in the cytosol and is bound
to inhibitory-B (IB), a regulatory protein (2, 5, 13). IB
phosphorylation on Ser 32 and Ser 36 by different regulatory kinases
dissociates IB from the NF-B complex, targeting IB for
degradation and NF-B for translocation to the nucleus. In the
nucleus, NF-B binds to DNA and activates the transcription of
several genes (2-5). An alternative mechanism for NF-B
activation has recently been described in reoxygenated Jurkat cells
after anoxic exposure and appears to involve IB tyrosine
phosphorylation and translocation of NF-B to the nucleus but without
IB degradation (10). Thus cell- and stimulus-dependent mechanisms
may be involved in NF-B activation.
The nucleus tractus solitarius (NTS) within the dorsocaudal brain stem
is the first central relay of peripheral chemoreceptor and baroreceptor
afferent inputs (11). During hypoxia, increased glutamate release
occurs within the NTS of awake rats, leading to activation of
N-methyl-D-aspartate
(NMDA) glutamate receptors, which are critical to the ventilatory and
cardiovascular responses to hypoxia (14, 16). Conversely, the
NMDA-receptor inhibitor {(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclopenten-5,10-imine hydrogen maleate} (dizocilpine maleate or MK-801) markedly
attenuates the ventilatory response to hypoxia (1, 14, 16). In
addition, increased nitric oxide (NO) release after NMDA-receptor
activation during hypoxia modulates the late phase of the hypoxic
ventilatory response (6-8, 15). Thus increased understanding of
intracellular regulatory processes in general, and particularly of the
transcription factors that are activated by NMDA glutamate-receptor
channel opening, could lead to identification of putative genes playing a functional role in the ventilatory response to hypoxia. An obvious candidate for such transcriptional regulation could be NF-B. However, the pattern of NF-B activation within brain stem regions subserving a respiratory task in response to hypoxia is currently unknown.
In this study, we examined whether a physiological hypoxic stimulus in
awake rats was associated with NF-B activation within the
dorsocaudal brain stem. Furthermore, we sought to determine whether
pharmacological inhibition of NMDA receptor or NO production would
modify the NF-B response to hypoxia in the dorsocaudal brain stem of
freely behaving rats.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animals and surgery.
The experimental protocols were approved by the Institutional Animal
Use and Care Committee. To determine the time course of NF-B
activation and IB phosphorylation, unrestrained Sprague-Dawley adult
rats weighing 200-350 g underwent a hypoxic challenge (10% O2-90%
N2) in a whole body
plethysmographic chamber for 0, 30, 60, 90, and 180 min. To assess the
effect of NMDA receptor or NOS blockade on baseline and hypoxic NF-B
activation and IB phosphorylation (IB-P) in the dorsocaudal brain
stem, animals were injected with MK-801 (3 mg/kg ip; RBI, Natick, MA)
or with NG-nitro-L-arginine methyl
ester (L-NAME, 100 mg/kg ip; Alexis, San Diego, CA) and were exposed to either room air
(RA) or to 10% O2-90%
N2 for 60 min (H).
70°C.
Approximately 5-10 mg of dorsocaudal brain stem tissue were
obtained from each rat.
Electrophoretic mobility shift assay (EMSA).
For each experiment, dorsocaudal brain stem tissue from two or three
rats exposed to H and RA (control) was minced on ice and homogenized
with a Dounce homogenizer in buffer A
[0.32 M sucrose, 3 mM magnesium chloride, 0.5 mM EGTA, 1 mM HEPES
0.1% Triton X-100, 0.5 mM phenylmethylsulfonyl fluoride (PMSF), 10 µg/ml aprotinin, and 10 µg/ml leupeptin]. Homogenates were
filtered and centrifuged at 4°C at 700 g for 10 min. Pellets were resuspended in lysis buffer B [20 mM HEPES,
125 nM sodium chloride, 5 mM magnesium chloride, 12% vol/vol glycerol,
5 mM dithiothreitol (DTT), 0.5 mM PMSF, 10 µg/ml aprotinin, and 10 µg/ml leupeptin], sonicated on ice for 15 s, and centrifuged at
14,000 rpm at 4°C. Protein concentration was determined by using a
Bio-Rad DC protein assay (Bio-Rad, Hercules, CA), and
samples were stored at 70°C until use.
B consensus oligonucleotide
5'-GGGGACTTTCCC-3' (Santa Cruz Biotechnology, Santa Cruz,
CA) was end labeled with [
-32P]ATP and
T4 polynucleotide kinase
(GIBCO-BRL Life Technologies, Gaithersburg, MD) and purified by using
Sephadex G-25 columns (Pharmacia Biotech, Uppsala, Sweden). Five
micrograms of protein from crude nuclear extract were mixed with the
labeled probe and buffer [10 mM HEPES, 7.2% vol/vol glycerol, 3 mM magnesium chloride, 3 mM DTT, 3 µl Nonidet P-40, 60 µg BSA, 360 µg spermidine, 1.5 µg poly(dI-dC) (Pharmacia
Biotech)] in a total volume of 20-µl and incubated to allow
NF-B binding to the probe. DNA-protein complexes were separated on
6% polyacrylamide gels (Novex, San Diego, CA), the gel was vacuum
dried, and labeled complexes were detected by autoradiography.
Competition assays were performed by using ×400 excess unlabeled
probe or NF-B mutant oligonucleotide (Santa Cruz Biotechnology).
Supershifts were performed by adding antibodies to the p50 and p65
subunits of NF-B to the binding mixture (Santa Cruz Biotechnology).
Western blots.
For each immunoblot analysis, dorsocaudal brain stem tissue from three
or four control (RA) and H rats was homogenized in 0.4 ml lysis buffer
(50 mM Tris, pH 7.5; 0.4% vol/vol Nonidet, 10% vol/vol glycerol, 150 mM sodium chloride, 2 µg/ml leupeptin, 1 µg/ml aprotinin, 10 mM
EDTA, 100 mM sodium fluoride, 1 mM vanadate), briefly sonicated, left
on ice for 1 h, and centrifuged at 14,000 rpm at 4°C for 10 min.
Protein concentration of the supernatants was determined by using a
Bio-Rad DC protein assay (Bio-Rad). Lysates were stored at
70°C until use. Then 75 µg protein per sample were
separated on 10% SDS-polyacrylamyde gels (Novex) and electroblotted
onto 0.2-µm nitrocellulose membranes. Membranes were blocked for 1 h
with 5% milk in 0.05% Tween-20 in Tris-buffered saline (TBS-T) and
incubated overnight with affinity-purified rabbit polyclonal antibodies
raised against phosphorylated IB-
(IB--P) (1:100)
or against total IB- (IB--T) [1:500;
PhosphoPlus-IB- (Ser 32) antibody kit; New England Biolabs,
Beverly, MA] in 5% milk in TBS-T. The antibody concentrations
were derived from preliminary experiments in which a control lysate
(New England Biolabs) was included and was observed to migrate to the
expected molecular weight and comigrate with the band obtained from the
dorsocaudal brain stem lysate. Membranes were extensively washed with
TBS-T and incubated with horseradish peroxidase-linked anti-rabbit
antibody in 5% milk in TBS-T. Excess antibody was washed out, and
proteins were visualized by using an enhanced chemiluminescence
detection method.
Data analysis.
As mentioned above, each sample consisted of pooled dorsocaudal brain
stem tissue harvested from 2-4 rats for each experimental condition. Four samples (time-course experiments for NF-B and experiments on IB-T and IB-P) or five samples (MK-801 and
L-NAME experiments for NF-B)
were assayed. The bands corresponding to NF-B, IB-T, and IB-P
were scanned, and densitometric values were subjected to two-way ANOVA
followed by Newman-Keuls post hoc tests for multiple comparisons. For
presentation purposes, the means of the individual ratios of
densitometric values for NF-B during hypoxia (10%
O2) divided by the densitometric
values for NF-B during normoxia (RA) were calculated for vehicle,
MK-801, and L-NAME treatments.
Similarly, the mean IB-P/IB-T ratios were calculated for the
three different treatments during normoxia [control (C) + RA,
MK-801 + RA, and L-NAME + RA], and the three treatments during hypoxia (C + H, MK-801 + H,
and L-NAME + H).
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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An increase in NF-B binding to DNA in the dorsocaudal brain stem of
rats after hypoxia was detected at 30 min, peaked at 60 min, and slowly
decreased at 90 and 180 min (Fig.
1A;
top, lanes
2-6). These results were consistently reproduced
in four different experiments.
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Phosphorylation of NF-B regulatory unit IB is associated with the
release of NF-B, allowing its translocation to the nucleus and
binding to DNA. Increases in IB-P at 30 min and decreases at 180 min
of hypoxia were consistently observed in Western blots of dorsocaudal
brain stem lysates (n = 4; Fig.
2A)
compared with normoxic rats, thereby confirming the EMSA findings.
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Administration of MK-801 to normoxic rats increased formation of
NF-B/DNA complex but markedly attenuated the increase in NF-B
binding to DNA after 60 min of hypoxia (Fig.
1B; n = 5). In contrast, L-NAME
treatment was associated with marked reductions in binding of NF-B
to DNA in the dorsocaudal brain stem of normoxic rats (Fig.
1B; n = 5). However, the increase in NF-B activation with 60 min of
hypoxia was not affected by
L-NAME (Fig.
1B). In addition, 60 min of exposure
to 5% CO2-balance RA did not
elicit significant changes in NF-B/DNA complex formation
(n = 2).
As with EMSA experiments, IB-P was mildly increased by MK-801 in the
pooled dorsocaudal brain stem tissue lysate of four groups of normoxic
rats (Fig. 2B). However, increases
in IB-P with hypoxia were markedly blunted by MK-801 (Fig.
2B). Administration of
L-NAME to normoxic rats
decreased IB-P but did not modify the hypoxia-induced increase in
IB-P (Fig. 2B).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The major findings of the present study include
1) the activation of NF-B in the
dorsocaudal brain stem of awake rats exposed to a relatively moderate
hypoxic stimulus and 2) the
modulation of such hypoxia-induced activation by NMDA-glutamate
receptors but not by NO synthase (NOS) activity.
Glutamate activation of NF-B has been previously observed in primary
neuronal cell cultures (12) and may also display some cell specificity.
Indeed, glutamate selectively induced NF-B activation in cerebellar
granules but not in astrocytes. In the latter, however, NF-B could
be activated by other stimuli, such as tumor necrosis factor- and
interleukin (9). It is now well established that NMDA receptors within
the NTS are critical for development of the ventilatory response to
hypoxia (1, 14, 16). Hypoxia will lead to increased peripheral
chemoreceptor afferent discharge, which is associated with increases in
NTS glutamate concentration (1, 14, 16), such that NF-B activation in the dorsocaudal brain stem during hypoxia could be related to the
increased glutamate release and NMDA-receptor channel activation that
occur within this particular brain stem region. It is important to
emphasize, however, that other stress-related pathways, as well as
other glutamate receptors, such as
-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) and
kainate glutamate receptors, could also contribute to overall NF-B
activation (17). Notwithstanding these possibilities, the attenuation
of NF-B activation by MK-801 and the absence of changes in NF-B
activity during hypercapnia are highly suggestive that NMDA receptors
are indeed involved in NF-B activation by hypoxia.
Activation of NMDA receptors may induce calcium elevations, either by
voltage-dependent calcium channel opening or by release of
intracellular calcium stores. Such a calcium signal will in turn bind
calmodulin and activate NOS to produce NO. Current evidence suggests
that NO influences neurotransmitter release through activation of
cGMP-dependent protein-phosphorylation cascades or, alternatively, rapidly diffuses to the presynaptic neuron, where it modulates glutamate release (19). Thus, NO could modify glutamatergic pathways
underlying the ventilatory response to hypoxia (6-8, 15). Within
the framework of such a NMDA-NO pathway, if IB-P were independent of
NOS activation, then L-NAME
should not modify NF-B activity. Alternatively, if NO
release modifies IB-P, L-NAME should reduce NF-B activation. We found that
L-NAME reduced basal NF-B
activity during normoxia but failed to modify the NF-B response to
hypoxia. In light of the putative role played by NO as a retrograde
messenger, the marked decrease in NF-B activation in the dorsocaudal
brain stem of unstimulated animals could be related to decreased
glutamate release from presynaptic neurons after
L-NAME administration rather
than being caused by a direct NO effect on NF-B activation. During
hypoxia, increased glutamate release would still occur in the
L-NAME-treated animals (15), and, therefore, increased NF-B activation would ensue. Thus, in view
of our findings, we postulate that IB-P and NF-B activation occur
upstream from NOS activation.
In a recent study (20), NO donors downregulated NF-B activity of
primary glial cell cultures, whereas increases in NF-B activity
occurred in astrocytes after 
4 h of treatment with
L-NMMA, a competitive NOS
inhibitor. Our observation of decreased NF-B activity during
normoxia appears to be in contradiction with such findings. However,
several factors may account for such disparities. First, the time frame
and experimental conditions differ markedly between these two studies.
Second, NOS inhibitors could have affected overall IB expression.
The levels of IB-T protein were not changed after
L-NAME administration in either
normoxia or hypoxia, with only IB-P being reduced by
L-NAME during normoxia, thus
excluding the possibility of enhanced protein degradation by the NOS
inhibitor in vivo. Third,
L-NAME induces a sustained
elevation of blood pressure in unrestrained rats (8), and this could
lead to significant attenuation of peripheral baroreceptor input to the
NTS, thereby reducing basal NF-B activity. Alternatively, as
mentioned above, L-NAME could have
reduced the retrograde positive- feedback release of glutamate, leading
to decreased NMDA-receptor activation, which in turn could have
attenuated basal NF-B activity.
In summary, we have shown that NF-B is activated by hypoxia in the
rat dorsocaudal brain stem, apparently through NMDA glutamate-receptor activation. The significance of such NF-B activation, as it may relate to identification of NF-B-regulated genes, which could be
induced in the rat dorsocaudal brain stem by increased glutamatergic synaptic transmission, remains to be elucidated. The recent description of cyclooxygenase-2 gene induction by NF-B during hypoxia in vascular endothelial cells (18) may represent an initial step in such
direction.
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ACKNOWLEDGEMENTS |
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This study was supported in part by grants from National Institute of Child Health and Human Development (HD-01072) and the Maternal and Child Health Bureau (MCJ-229163) and by a Career Development Award from the American Lung Association (CI-002-N).
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FOOTNOTES |
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Address for reprint requests: D. Gozal, Sect. of Pediatric Pulmonology, SL-37, Dept. of Pediatrics, Tulane Univ. School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112 (E-mail: dgozal{at}tmcpop.tmc.tulane.edu).
Received 13 November 1997; accepted in final form 12 March 1998.
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Introduction
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Discussion
References
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