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1 Departments of Pharmacology and Toxicology, 2 Anatomy and Cell Biology, and 3 Obstetrics and Gynaecology, Queen's University, Kingston, Ontario, Canada K7L 3N6
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Carbon monoxide (CO), which is formed endogenously from heme catalyzed by heme oxygenase (HO), is proposed to play a role in vascular control. The mRNA and protein expression of the inducible isoform of HO (HO-1) increases in response to hypoxia, and it has been assumed that HO activity also increases. This assumption requires evaluation because the catalytic activity of HO requires three molecules of O2 for each molecule of CO formed from heme, and HO activity may be limited by O2 availability. To test the hypothesis that low physiological O2 concentrations limit HO activity, heme-derived CO formation by microsomal fractions of homogenates of chorionic villi of human placentas was determined after exposure to 0, 1, 5, or 21% O2. Results revealed that HO activity was directly dependent on O2 concentration. Thus, although hypoxia may increase HO protein and mRNA expression, there is a progressive decrease in HO activity with decreasing O2 concentration and the dependence of HO activity on O2 concentration is similar in chorionic villi from noninfarcted areas of preeclamptic and normotensive placenta.
heme oxygenase-1 expression; carbon monoxide; hypoxia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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HEME OXYGENASE (HO) catalyzes the breakdown of heme in the presence of O2 and reduced NADP (NADPH) to form carbon monoxide (CO), biliverdin, and iron. Biliverdin is subsequently converted to bilirubin by biliverdin reductase. Both biliverdin and bilirubin have been shown to be potent antioxidants in several tissues (19) and CO has been proposed to play a role in cell-cell communication and in the relaxation of various blood vessels (11, 22, 23, 26). Earlier studies (16, 21), determining the stoichiometry of the HO reaction, demonstrated that HO consumed three molecules of O2 and two molecules of NADPH for every molecule of heme biotransformed.
There are two predominant isoforms of HO: HO-1 is the inducible isoform, whereas the expression of HO-2 is constitutive, and hence these isoforms are responsible for basal HO activity in cells. The expression of HO-1 can be increased in response to several cellular stresses, including exposure to heme, heavy metals (i.e., Cd2+ and Co2+), trivalent arsenicals, heat shock, ischemia, radiation, hypoxia, hyperoxia, endotoxin, inflammatory cytokines, prostaglandin A1, and hormones, as well as glutathione depletion (see Ref. 10 for a review). It is thought that HO-1 is responsible for the marked increase in HO activity during several pathological conditions and therefore is categorized as a stress enzyme designated as heat shock protein 32 (HSP32) (7).
It has been postulated that the rapid induction of HO-1 and the inhibitory effect of CO on the transcription of certain hypoxia-inducible genes provide a cytoprotective role for HO within the human placenta (1). Endogenous CO formation has been measured in dissected chorionic villi of term human placenta (14). CO has also been shown to play a role in the maintenance of placental vascular tone (9) and, to this end, a dysfunction in the HO-CO system has been associated with preeclampsia, a pathophysiological condition characterized by compromised uteroplacental blood flow and localized regions of placental hypoxia (6). Because O2 is required for HO enzymatic activity, we propose that such activity is deficient in disease states characterized by tissue hypoxia such as preeclampsia.
In the present study, our first objective was to determine the dependence of HO activity on O2 availability using the microsomal fraction of homogenate of chorionic villi from full-term human placenta as a model system. The second objective was to determine whether HO activity in the presence of various O2 concentrations is altered in chorionic villi of placentas from preeclamptic pregnancies compared with gestational age-matched normotensive pregnancies.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Reagents and solutions.
Hemin, ethanolamine, bovine serum albumin (BSA), and NADPH were
obtained from Sigma (St. Louis, MO). All other chemicals were at least
reagent grade and were obtained from BDH (Toronto, ON, Canada). The
stock solution of methemalbumin (1.5 mM hemin and 0.15 mM BSA) was
prepared as previously described (24). Briefly, hemin was
dissolved in 0.5 ml of aqueous 10% (wt/vol) ethanolamine. BSA
dissolved in 2 ml of deionized water was added to the hemin solution.
The volume was made up to 7 ml and slowly adjusted to pH 7.4 with 1 M
HCl and vigorous stirring. The final volume for the stock solution was
adjusted to 10 ml with deionized water. The methemalbumin stock
solution was prepared with the laboratory lights turned off and was
stored at 
20°C for up to 1 mo.
Preparation of microsomal fraction of homogenate of chorionic villi of human placenta. Human placentas of gestational age 37-42 wk were obtained from elective caesarean deliveries of uncomplicated and gestational age-matched preeclamptic pregnancies at Kingston General Hospital. Within 1 h of delivery, samples of chorionic villi of a placental cotyledon were dissected. This region was selected because it is highly vascularized and has been previously shown to possess high levels of HO activity (13). Noninfarcted areas of chorionic villi were identified based on gross morphology and the absence of calcium deposits, which characterize areas of infarction.
To isolate microsomal fractions, 10% (wt/vol) homogenate of chorionic villi was prepared in ice-cold homogenizing buffer composed of (in mM) 20 KH2PO4, 135 KCl, and 0.10 EDTA (adjusted to pH 7.4 at 4°C with 1 M KOH) with the use of an ultrasonic probe (Sonic Dismembrator, Fisher Scientific; Toronto, ON, Canada). Microsomal fractions of the homogenates were obtained by centrifugation at 10,000 g for 20 min at 4°C, followed by centrifugation of the supernatant at 100,000 g for 60 min at 4°C. The 100,000 g pellet (microsomal fraction) was resuspended in 100 mM KH2PO4 buffer (adjusted to pH 7.4 with 1 M KOH) using a Potter-Elvehjem homogenizing system. The microsomal fraction was divided into equal aliquots, placed into microcentrifuge tubes, and stored at80°C for up to 2 mo. HO enzymatic activity
remains stable under these storage conditions (B. E. McLaughlin,
unpublished observations). Protein concentrations of the microsomal
fractions were determined by the Biuret method (5), which
was modified as described previously (12).
Measurement of HO enzymatic activity in microsomal fractions of
homogenates of chorionic villi.
HO activity in the microsomal fractions of chorionic villi homogenate
was determined by measuring the rate of CO formation during the
NADPH-dependent oxidation of heme, as originally described by Vreman
and Stevenson (25) and modified by Cook et al.
(4). For chorionic villi of each placenta, HO activity was
determined in the presence of four different O2
concentrations (0, 1, 5, or 21%). To each of four 3.5-ml amber glass
vials (Chromatographic Specialties; Brockville, ON, Canada) was added
100 mM KH2PO4, pH 7.4, 0.2 mg microsomal
protein, and methemalbumin (final concentration of 25 µM hemin and
2.5 µM BSA) in a final volume of 1 ml. While kept on ice, each vial
was sealed with a Teflon-lined silicon septum and a screw cap
(Chromatographic Specialties), and the headspace gas was purged with a
gas mixture containing 1% O2 (balance N2;
certified free of CO contamination) introduced by means of a needle
system used to pierce the septum, while the contents were stirred
constantly. The samples were then preincubated for 5 min in the dark at
37°C, in a shaking water bath. NADPH (0.5 mM) was added to three of
the four vials, the headspace gas was displaced for 10 s with 1%
O2, and the incubation was continued for another 15 min.
The fourth vial, to which no NADPH was added, was used as a blank. The
reaction was stopped by the placement of all vials, except one
containing NADPH, on pulverized dry ice (78°C), where they remained
for 30 min until the headspace gas was analyzed for CO content. The
remaining reaction vial was stored at 4°C, and the reaction mixture
from this sample was injected onto a blood gas analyzer (model ABL 5, Radiometer Copenhagen) to determine the PO2.
The above protocol was repeated using each of 0, 5, and 21%
O2 concentrations. For each O2 concentration, CO production was corrected for the CO produced in the reaction vial
that contained no NADPH (blank). To determine total HO activity in the
microsomal fractions of homogenates of chorionic villi of human
placenta, a sample was prepared that was not purged with gas before the
HO enzymatic reaction but was equilibrated with ambient air. This was
done to verify that our experimental treatment, which included purging,
did not exhibit altered HO activity.
Data analysis. The HO enzymatic activity in the microsomal fractions of chorionic villi homogenates incubated at each O2 concentration was expressed as nanomoles CO formed per milligram of protein per hour. The data are presented as group means ± SD for four normotensive placentas and five preeclamptic placentas. Parametric statistical analysis of the HO activity data of microsomal fraction of chorionic villi homogenate of normotensive placentas for the different O2 concentrations was conducted by one-way repeated-measures analysis of variance. For a statistically significant F statistic (P < 0.05), a post hoc Newman-Keuls test was conducted to determine which experimental groups were statistically different (P < 0.05). Comparison of the HO activity in chorionic villi from uncomplicated and preeclamptic pregnancies was conducted by two-way analysis of variance for differences in HO activity between the two pregnancy conditions and among the three O2 concentrations. For a statistically significant F statistic for O2 concentration (P < 0.05), a one-way repeated-measures analysis of variance was conducted, followed by a Newman-Keuls post hoc test to determine which experimental groups were statistically different (P < 0.05). For a statistically significant F statistic between the two pregnancy conditions, a Student's t-test was used. HO enzymatic activity values for tissues obtained from normotensive and preeclamptic pregnancies were also analyzed as a scatterplot. The curve of best fit was determined separately for data collected from uncomplicated and preeclamptic placentas by using nonlinear regression analysis and the Michaelis-Menten constant (Km) for PO2 was calculated.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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It has been assumed that the levels of expression of HO-1 mRNA and protein correlate with the activity of the enzyme. In some situations of cellular stress, this may be true. However, because three molecules of O2 are required for each molecule of CO and biliverdin generated during heme metabolism, we hypothesized that regardless of the levels of HO enzyme present, CO production is reduced when O2 levels are low.
Therefore, using the microsomal fraction of homogenates of chorionic
villi from term human placenta as a model system, the first objective
of this study was to determine the dependence of HO (HO-1 and HO-2)
activity on O2 availability. Accordingly, the headspace gas
of sealed reaction vials, containing human chorionic villi microsomal
fraction and a source of heme, was replaced with 0, 1, 5, or 21%
O2 (balance N2). The mean
PO2 values achieved and corrected to
atmospheric PO2 of 154 mmHg are shown in Fig. 1. From the PO2
values obtained from control samples equilibrated in ambient air, a
correction factor was determined for that data set and was applied to
subsequent PO2 measurements obtained. The corrected PO2 values of the reaction mixtures
were 18.0 ± 2.4, 25.9 ± 3.9, 53.1 ± 5.7, and
166.1 ± 25.2 mmHg when the headspace gas was purged with 0, 1, 5, and 21% O2, respectively. Therefore, by purging the
headspace gas with decreasing amounts of O2, we were able
to decrease the PO2 of the reaction mixture.
The HO enzymatic activity at these PO2 values
also decreased in a corresponding manner (Fig.
2), and the HO enzymatic activities of
the samples purged with 0, 1, 5, and 21% O2 were
significantly different from each other (P < 0.05).
There was no significant difference in HO activity between samples
exposed to ambient air compared with samples for which the headspace
gas was purged with 21% O2 (data not shown). The
HO-catalyzed oxidation of heme to biliverdin is a three-step process,
each of which requires one molecule of O2 (8).
Therefore, diminished O2 concentration will likely lower HO
activity, thereby decreasing the formation of biliverdin and two
intermediates in biliverdin formation. In addition, HO activity would
be controlled by heme and NADPH concentrations as well as by the
activity of cytochrome P-450 reductase. It is also likely that the concentrations of heme and NADPH and cytochrome
P-450 reductase activity would be influenced by decreased
O2 concentrations.
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The second objective was to determine whether HO activity in the
presence of various O2 concentrations is altered in
chorionic villi of placentas obtained from preeclamptic pregnancies
compared with gestational age-matched normotensive pregnancies. The
impaired uteroplacental perfusion that occurs in preeclampsia due to
maladaptation of the uteroplacental spiral arterioles results in
localized regions of hypoxia (6). We assessed the
relationship between PO2 and HO activity in
chorionic villi microsomal preparations obtained from noninfarcted
areas of placentas from preeclamptic pregnancies and found it to be
similar to that in chorionic villi microsomal preparation from
noninfarcted areas of placentas from normotensive women (Fig.
3). Samples equilibrated in ambient air
were also tested and compared. There was no statistically significant
difference when group means for HO activity of the microsomal fraction
of homogenates of chorionic villi of placentas from preeclamptic pregnancies were compared with group means of HO activity of the microsomal fractions of homogenates of chorionic villi isolated from
placentas of normotensive women at each O2 concentration (Fig. 3). Moreover, nonlinear regression analysis revealed a
significant correlation between HO activity and
PO2 of the reaction mixture (Fig.
4) for each of preeclamptic and
normotensive pregnancies. From each curve of best fit, the
Km for PO2 was
determined to be 43 ± 15 and 52 ± 18 mmHg for HO enzymatic
activity in the microsomal fraction of chorionic villi homogenate from
normotensive and preeclamptic placentas, respectively.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In a recent study, Carraway and colleagues (2) examined HO-1 protein and mRNA expression as well as HO enzymatic activity in the rat lung after exposure in an altitude chamber to 395 mmHg (17,000 ft) for up to 21 days. These workers found that the expression of HO-1 protein increased in rats exposed to hypoxia for the first 7 days and decreased thereafter. Moreover, the enzyme activity was elevated only after 1 day of hypoxia and then returned to control values thereafter. The authors attribute their findings to the fact that the Km for PO2, reported by them as 8 mmHg, is an important predictor of the behavior of the enzyme during hypoxia. Both in vivo and in vitro studies in the placenta and other tissues have shown an increase in HO-1 mRNA and protein expression in response to hypoxia, and it has been assumed that the increase in HO-1 protein expression and/or HO-1 mRNA is accompanied by an increase in HO activity (3). Throughout pregnancy, O2 levels in the placenta have been reported to change from ~17 mmHg in the first trimester to 60 mmHg after week 13 of gestation (18). Thus one can expect corresponding fluctuations in HO enzymatic activity. Moreover, a variety of tissues, including malignant tumors, have been shown to exhibit large PO2 gradients (20). Unfortunately, in the vast majority of studies, HO activity has been measured in the presence of ambient O2 levels, which are extremely high and nonphysiological, whereas the enzyme in situ functions in the presence of much lower O2 concentrations. The results of the present study suggest that the actual levels of HO enzymatic activity in most tissues are lower than previously measured.
Other studies (3, 15) of term human placenta report the existence of HO-1 mRNA and protein but do not report enzymatic activity. These studies make the assumption that the existence of HO protein in their experimental tissue preparation indicates a functional enzymatic system whereby CO, biliverdin, and iron are formed from the HO-catalyzed oxidation of heme, and a role for each of these products is inferred. Because of our studies, some of the conclusions reached by previous investigators might require reconsideration.
Although it has been proposed that CO generated from HO catalytic activity plays a role in the regulation of placental blood flow (9), the function of HO in the maintenance of placental homeostasis may be broader. As indicated earlier, biliverdin and subsequently bilirubin are products of HO-mediated heme catabolism, which have potent antioxidant properties. Thus HO may also play an important role in protecting the placenta and the fetus from oxidative stress damage that could occur during the establishment of the uteroplacental circulation at the end of the first trimester (18) or during conditions characterized by abnormal uteroplacental blood flow, like preeclampsia.
In conclusion, the present study demonstrates that in the microsomal fractions of homogenates of chorionic villi from term human placenta, 1) HO activity decreases with decreasing O2 availability and 2) the direct dependence of HO activity on O2 concentration is similar in chorionic villi from noninfarcted areas of preeclamptic and normotensive placentas.
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ACKNOWLEDGEMENTS |
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The authors thank Dr. Gendie Lash for collection of the placentas, Dr. Henk Vreman for collaboration and use of the reduction-gas analyzer, and Brian McLaughlin for assistance in this study.
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FOOTNOTES |
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This work was supported by the Heart and Stroke Foundation of Ontario Grants NA-4438 and T-3361.
Address for reprint requests and other correspondence: C. H. Graham, Dept. of Anatomy and Cell Biology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6 (E-mail: grahamc{at}post.queensu.ca).
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.
First published February 21, 2002;10.1152/ajpheart.01084.2001
Received 10 December 2001; accepted in final form 18 February 2002.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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