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1 Departments of Surgery, Medicine, and Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York 10032; 2 Department of Pathology, The University of New Mexico School of Medicine, Albuquerque, New Mexico 87131; and 3 Department of Immunology and Vascular Biology, Scripps Research Institute, La Jolla, California 92037
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Hypoxia induces complex adaptive responses. In this report, induction of early growth response-1 (Egr-1) transcripts in lungs of mice subjected to hypoxia is shown to be dose and time dependent. Within 30 min of hypoxia, Egr-1 transcripts were ~20-fold elevated in 6% oxygen, ~5.2-fold increased by 10% oxygen, and returned to the normoxic baseline by 12% oxygen. Time course studies up to 48 h showed a biphasic profile with an initial steep rise in Egr-1 transcripts after 0.5 h of hypoxia and a second elevation beginning after 20-24 h. Hypoxic induction of Egr-1 was paralleled by enhanced expression of the downstream target gene tissue factor. Egr-1 and tissue factor antigen were visualized in bronchial and vascular smooth muscle and in alveolar macrophages. Egr-1 has the capacity to modulate expression of genes involved in the remodeling of the extracellular matrix and properties of smooth muscle, thus possibly contributing to the pulmonary response to chronic hypoxia.
transcription factor; hypoxia gene expression; Sp1; tissue factor
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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EARLY GROWTH RESPONSE (Egr)-1 is a zinc
finger transcription factor in a multigene family that includes
Egr-2, Egr-3, Egr-4, and WT1 (Wilm's
tumor-suppressor gene) (8, 23, 34). It was first identified because of
a characteristic rapid induction and subsequent decay after cells were
exposed to stimuli associated with growth and differentiation. Earlier
in vitro studies demonstrating that differentiation of cells along a
macrophage lineage depended on Egr-1 expression were consistent with an
important role in development (17, 24). However, these initial
suggestions of Egr-1 function contrasted to the phenotype of homozygous
Egr-1 null mice (19, 20). These animals grew and developed normally (including in monocyte-macrophage differentiation), except for infertility in females due to deficient transcription of luteinizing hormone-
. Thus functional effects of Egr-1 were more likely to be
revealed in the response to stress than under homeostatic conditions. Consistent with this view, cell culture studies showed Egr-1 to be
involved in expression of a range of "inducible" genes associated with the host response, such as intercellular adhesion molecule-1, tumor necrosis factor-
, macrophage colony-stimulating factor, transforming growth factor-, platelet-derived growth factors A and
B, nuclear factor-
B, p105, and so forth (4, 11, 13, 15, 21, 22, 32,
41).
The first vascular stress responses in which Egr-1 was clearly shown to contribute involved mechanical damage to the vessel wall (14, 29). Denuding injury to rat aortas demonstrated expression of Egr-1 in the endothelium at the wound edge and upregulation of downstream target genes, such as platelet-derived growth factor (14). A relevant in vitro system, scrape injury applied to confluent endothelial cell cultures, showed that release of fibroblast growth factor 2 consequent to physical disruption of the monolayer was the stimulus for induction of Egr-1 (28). These observations were further extended by studies with a DNA enzyme that specifically cleaved Egr-1 mRNA (29) and suppressed rat carotid artery intimal thickening after balloon injury.
Another quite distinct situation concerns induction of Egr-1 in the lung after exposure to acute hypoxia (37-39). Our work has demonstrated that severe hypoxia, an environment with 6% oxygen, causes rapid upregulation of Egr-1 in smooth muscle cells and mononuclear phagocytes in the lung. Although Egr-1 induction occurred rapidly, within 30-45 min of oxygen deprivation, it was shown to involve de novo biosynthesis. The possible contribution of Egr-1 to the pathobiology of acute hypoxemic vascular injury was demonstrated by analyzing expression of the procoagulant regulator tissue factor. In vitro experiments showed that tissue factor induction occurred at the transcriptional level and was mediated by Egr-1 interacting with its cognate DNA binding sites in the serum response region of the promoter (7). In vivo, hypoxia caused expression of tissue factor in the hypoxic lung, and this resulted in vascular fibrin accumulation. A cause-effect relationship between hypoxia-mediated Egr-1 expression, induction of tissue factor, and fibrin deposition in pulmonary blood vessels was shown in homozygous Egr-1 null mice. In contrast to wild-type controls, Egr-1 null animals subjected to hypoxia did not display tissue factor expression or vascular fibrin deposits. Egr-1 induction in hypoxia was shown to be independent of hypoxia-inducible factor (HIF) 1 (38), the best characterized adaptive mechanism triggered by oxygen depletion (30).
These studies suggested a possibly distinct contribution of Egr-1 to the biology of the cellular response to hypoxia. However, Egr-1 induction had been studied only under conditions of severe oxygen depletion (6% oxygen) and only for brief periods (up to 6 h). The experiments in this study were designed to examine expression of Egr-1 in lungs of mice exposed to a range of oxygen concentrations (6-20%) and time points (30 min to 48 h) to better assess possible physiological and/or pathophysiological roles for this transcription factor in the hypoxemic lung.
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EXPERIMENTAL PROCEDURES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Induction of hypoxia. Mice were subjected to hypoxia in accordance with a protocol approved by the Institutional Animal Care and Use Committee at Columbia University. Female C57BL/6 mice (3-4 mo of age) were obtained from Jackson Laboratories (Bar Harbor, ME). Normobaric hypoxia (n = 5 mice per experimental group) was induced for the indicated times by the regulated addition of nitrogen to a chamber equipped with circulating fans, carbon dioxide and ammonia elimination systems, and an on-line oxygen sensor (Horiba, Kyoto, Japan) (18). The environment within the chamber (including temperature and humidity) was regulated by a custom-built interface (K+K Interface), which used a computer-driven environmental control program. This system resulted in the indicated oxygen concentrations ±0.2%. Mice placed in the chamber in their usual cages were allowed free access to food and water, and the system parameters were adjusted to the indicated final oxygen concentration. Animals exposed to hypoxia were not in distress (although, at more severe levels of oxygen deprivation, they were tachypneic), and there was no mortality even at the lowest oxygen tension (6%) and the longest incubation period (48 h). At the indicated times, animals were killed, and tissues were studied as described below.
Northern analysis.
Tissue was cut into small pieces, immersed in TRIzol (GIBCO BRL, Grand
Island, NY), and homogenized; total RNA was extracted and
electrophoresed on 0.8% agarose gels. RNA was transferred to
Duralon-UV membranes (Stratagene), and the latter were then hybridized
with 32P-labeled cDNA probes for mouse Egr-1 (39), Sp1
(39), tissue factor (39), or HIF-1 (31). Hybridization
of blots with 32P-labeled -actin was used as an internal
control for RNA loading.
Immunohistochemistry. Lung tissue was cut into small pieces, washed with phosphate-buffered saline (pH 7.0), fixed in formalin, and embedded in paraffin (37, 40). Sections were first stained with primary antibodies: rabbit anti-Egr-1 IgG (8 µg/ml; Santa Cruz) and anti-tissue factor IgG (63 µg/ml) (18). Sections were then incubated with secondary antibody, an affinity-purified peroxidase-conjugated anti-rabbit IgG (Sigma).
Statistical analysis of data. Northern blots were exposed to X-ray film, and, after the film was developed, the entire blot was scanned into a Macintosh computer using a Hewlett-Packard Scanjet 2cx scanner and Adobe Photoshop software. Data were subsequently transferred to Molecular Imager analysis software (Bio-Rad), and the density of each band was calculated on the basis of comparison with the intensity of the corresponding control band (the corresponding band in normoxia or at time 0). Each experiment was repeated a minimum of three times, and the mean relative densities (±SE) are shown. A representative blot from the series of blots performed is shown in Figs. 1-3. Significant differences between groups were detected using ANOVA for unpaired variables, with post hoc comparisons performed using Tukey's procedure. P < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Dependence of Egr-1 mRNA expression on oxygen tension.
Previous studies demonstrated that exposure of mice (C57BL/6) to severe
hypoxia (6%) caused a rapid elevation of Egr-1 transcripts (38).
However, the relationship between Egr-1 expression and the degree of
hypoxia has not been analyzed. To address this issue, mice were placed
in environments with different concentrations of oxygen (6, 6.5, 7, 8, 9, 10, 12, and 15% and ambient), and expression of Egr-1 transcripts
in the lung was assessed after 30 min (Fig.
1A). Egr-1 mRNA was strongly
elevated at 6, 6.5, and 7% oxygen and began to fall off at 8 and 9%,
approaching baseline (normoxic) levels by 12%. Densitometric analysis
(Fig. 1B) of several gels similar to those in Fig. 1A
showed an ~20-fold increase in Egr-1 mRNA at 6% oxygen, which
declined to ~10-fold at 8% oxygen and which was only slightly above
the normoxic baseline (~5.2-fold) at 10% oxygen. When the same blot
was hybridized with a 32P-labeled probe for Sp1, a
transcription factor that also interacts with a GC-rich DNA binding
motif (often overlapping with Egr-1 DNA binding sites) (1, 2, 10, 15),
no increase in Sp1 mRNA was detected in hypoxic lung (Fig. 1, C
and D). Similarly, levels of -actin mRNA were unchanged in
samples harvested from normoxic and hypoxic animals (Fig. 1. E
and F). Experiments performed to detect HIF-1 transcripts in
hypoxic lung under the same conditions demonstrated no increase at any
of the oxygen tensions tested (6-15% oxygen; not shown).
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Dependence of Egr-1 mRNA expression on the duration of hypoxia.
Although the 30-min time point appeared to provide a sensitive index of
acute induction of Egr-1 transcripts in hypoxic lung (Fig. 1A),
it was essential to undertake a time course study. For this purpose,
experiments were performed at two oxygen concentrations (6 and 10%)
and a series of times up to 48 h (0.5, 1, 2, 4, 6, 8, 12, 16, 18, 24, and 48 h) (Fig. 2). At 6% oxygen, Egr-1
transcripts displayed an early peak at 0.5 h, slowly returning to the
normoxic baseline by 12 h (Fig. 2, A-I and A-II).
However, after 20 h of hypoxia, Egr-1 transcripts began to increase
again, and this elevation continued at 24 and 48 h. Levels of Sp1 and
-actin transcripts were unchanged throughout the times tested in 6%
oxygen (Fig. 2, A-III to A-VI). At 10% oxygen, the
0.5-h peak of Egr-1 transcripts in the lung was less pronounced, but
the biphasic response to hypoxia was still evident (Fig. 2, B-I
and B-II). The second phase of Egr-1 induction was observed
after 24 and 48 h, as the level of transcripts clearly rose above the
normoxic baseline by 48 h (Fig. 2, B-I and B-II). Sp1
and -actin mRNA were not altered by exposure to 10% oxygen (Fig. 2,
B-III to B-VI).
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-actin mRNA levels were unchanged (Fig. 3,
C, D, G, and H), Egr-1 transcripts
displayed dose-dependent modulation; for example, at 6 and 10% oxygen,
they were approximately ninefold and approximately threefold above
normoxia, respectively (Fig. 3, A and B). Thus the
increase in Egr-1 mRNA in hypoxic lung during the second phase of Egr-1
induction was also dose dependent. To assess sites of Egr-1 expression
after 48 h of hypoxia, immunohistological analysis was performed (Fig.
4A). Although Egr-1 antigen was
virtually undetectable in normoxic lung (Fig. 4A, normoxia), in
the presence of severe hypoxia (6% oxygen), Egr-1 was evident in
vascular smooth muscle (Fig. 4A-I), bronchial smooth muscle
(Fig. 4A-II), alveolar macrophages (Fig. 4A-III; note
arrows), and bronchial epithelium (Fig. 4A-II) at the 48-h time
point. Immunoreactivity in bronchial epithelium and smooth muscle and
vascular smooth muscle was not uniform, as evidenced by considerable
cell-to-cell variation in staining intensity. With more mild hypoxia
(Fig. 4A, 10% oxygen), Egr-1 antigen was still detectable in
the same locations, but the intensity of staining was reduced compared
with 6% oxygen.
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Expression of tissue factor in hypoxic lung. To assess the possible functional significance of Egr-1 expression in hypoxic lung, its activation of a downstream target gene was studied. Previous work has shown that expression of tissue factor is regulated by Egr-1 in the lung consequent to acute hypoxia (up to 6 h) (39). Thus tissue factor was selected as a readout for Egr-1 functional activity at the different oxygen concentrations after 48 h of hypoxia. Consistent with the concept that hypoxia-induced expression of Egr-1 had effects that lasted beyond the acute period, increased levels of tissue factor were observed. Expression of tissue factor transcripts in hypoxic lung was dependent on the oxygen tension; mRNA levels were highest at 6% (~6-fold above the normoxic baseline) and appeared to progressively decline with higher oxygen concentration, although at 10% oxygen they were ~2.2-fold above normoxia (Fig. 3, E and F). The effect of oxygen concentration on expression of tissue factor transcripts appeared, in general, to parallel that for Egr-1 (Fig. 3, A and B). Tissue factor antigen (Fig. 4B) was also observed in hypoxic lung compared with virtually no identifiable tissue factor in normoxic samples. Figure 4B shows that there was increased expression of tissue factor in hypoxic vascular smooth muscle, with greater staining intensity at 6% oxygen compared with at 10% oxygen (although, of course, this is not a quantitative technique). Enhanced expression of tissue factor in alveolar macrophages and bronchial smooth muscle from hypoxic lung was also observed (not shown). These data indicate that the distributions of Egr-1 and tissue factor antigen in hypoxic lung overlap.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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The results of our studies indicate that Egr-1 induction in hypoxic
murine lung occurs over a range of oxygen concentrations, not only in
the presence of the most severe hypoxia (
6% oxygen). Furthermore,
the temporal pattern of Egr-1 expression is biphasic, with an initial
peak after 0.5 h of hypoxia and a second phase beginning after
~20-24 h. With more moderate hypoxia (an oxygen concentration of
9-10%), the initial peak of Egr-1 transcripts at 0.5 h was less
striking, but there was still a second phase of Egr-1 induction after
24 h.
Immunohistological analysis of hypoxic lung indicated that Egr-1 was
especially evident in smooth muscle of the walls of bronchi and
vasculature as well as in alveolar macrophages, cell types critical for
tissue remodeling in response to chronic hypoxia. Furthermore, the list
of genes subject to regulation by Egr-1 is provocative. Our initial
studies have focused on tissue factor. Although this procoagulant
regulator has a central role in pulmonary vascular fibrin formation in
the setting of acute hypoxia (39), the significance of procoagulant
events in the pulmonary response to chronic hypoxia is unclear (10).
However, these studies need to be extended to consider the possibility
that other genes, previously shown to be regulated by Egr-1 in vitro,
might be involved. For example, pulmonary hypertension is associated
with increased production of extracellular matrix components, including
tenascin-C (6, 12, 27). A previous study has shown the presence of
functionally active Egr-1 sites in the murine tenascin promoter (5).
Matrix metalloproteinases have also been shown to contribute to the
vascular hypertrophy that accompanies pulmonary hypertension (12, 26, 27). Membrane type 1 metalloproteinase (MT1-MMP or MMP14), a potentially important contributor to remodeling of extracellular matrix, has been shown to be regulated in culture by Egr-1 (9). In this
context, endothelial and serum factors, including apolipoprotein A-I,
tether elastin to smooth muscle cells, inducing serine elastase activity (33). Apolipoprotein A-I has also been shown to be under
control of Egr-1; this is partly based on comparative studies in
Egr-1(
/) mice and littermate-matched Egr-1(+/+) controls (44). Egr-1-mediated regulation of transforming growth factor- (16),
as well as insulin-like growth factor II (3) and the insulin-like
growth factor receptor 1 (35, 36), may also be relevant to changes in
expression of extracellular matrix components and smooth muscle cell
properties in hypoxic lung. In vivo studies will be required to
determine whether products of these genes are expressed in response to
hypoxia and subject to control by Egr-1. Furthermore, evaluation of the
expression of other genes, such as those related to vasoreactivity,
will be important for comparison of Egr-1 null and wild-type mice.
Increased expression of HIF-1 transcripts was not demonstrated by
Northern blotting at any of the time points or oxygen concentrations (6-10%) in our studies, based on analysis of the same samples (not shown) described above for Egr-1. This is consistent with increased expression of HIF-1 in ferret lungs ventilated with 0-1.3% oxygen but not at higher oxygen concentrations (42). However, it is clear that HIF-1 participates in the pulmonary vascular response to chronic hypoxia elicited in the presence of 10%
oxygen, as shown by the blunted response in heterozygous null
HIF-1(+/) mice. Development of right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling after exposure to hypoxia was clearly delayed in HIF-1(+/) mice
(43). In view of these observations, our inability to detect HIF-1 transcripts in hypoxic lung might be because an important component of
HIF-1 regulation occurs posttranslationally (30, 31). However, it is
well known that there is also significant control of HIF-1 during
hypoxia at the transcriptional level (30, 31). This suggests the likely
possibility that our assays lacked sufficient sensitivity to detect
small changes at low levels of gene expression. In terms of HIF-1
transcripts in hypoxic lung, increased levels of mRNA have been
observed in a previous study in rats placed in an atmosphere with 10%
oxygen for 2 wk (25), consistent with elevated expression of this
component of the HIF-1 heterodimer at a considerably later time point.
Our present results indicate that expression of Egr-1 can be detected
at this same oxygen concentration (10%) in total RNA extracted from
mouse lungs.
Together, these data indicate that increased pulmonary expression of Egr-1 in mice subject to hypoxia, with oxygen concentrations ranging from 6 to 10%, occurs in a graded fashion and with a biphasic time course. Egr-1 transcripts are detectable at each of these oxygen concentrations, although they are undetectable at 15-20% oxygen. Furthermore, expression of an Egr-1 downstream target gene, tissue factor, was also observed, suggesting that Egr-1 was transcriptionally active in the hypoxic lung. These findings suggest the relevance of examining the possible impact of Egr-1 on the vascular response to chronic hypoxia.
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ACKNOWLEDGEMENTS |
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This work was supported by grants from the National Institutes of Health (HL-63967, HL-59488, and AG-16233) and the Surgical Research Fund.
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FOOTNOTES |
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D. J. Pinsky is an Established Investigator of the American Heart Association.
Original submission in response to a special call for papers on "Hypoxia Influence on Gene Expression."
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S.-F. Yan, Dept. of Surgery, P&S 11-420, College of Physicians and Surgeons, Columbia Univ., 630 West 168th St., New York, NY 10032 (E-mail: sy18{at}columbia.edu).
Received 18 February 2000; accepted in final form 23 March 2000.
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RESULTS
DISCUSSION
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