© 2000 American Heart Association, Inc.
Cellular Biology |
Human Vascular Smooth Muscle Cells but Not Endothelial Cells Express Prostaglandin E Synthase
From the Laboratory of Inflammation Mediators (M.S., M.C., J.-R.E.,
L.V.), Institute of Research of Hospital Santa Creu i Sant Pau, Barcelona, and
Centro de Biología Molecular "Severo Ochoa" Centro Superior
de Investigaciones Cient
icas (M.A.I.),
Madrid, Spain.
Correspondence to Dr Luís Vila, H.S. Creu i S. Pau (Antigua Guardería), S. Antonio Ma Claret 167, 08025 Barcelona, Spain. E-mail luisvila{at}retemail.es
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Abstract |
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Abstract—In a previous work, we postulated that endothelial cells possess only the following 2 enzymes involved in prostanoid synthesis: cyclooxygenase and prostacyclin synthase. The present work focused on investigating the expression of prostaglandin (PG) E synthase (PGES) in vascular cells. After incubation of vascular smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) with [14C]arachidonic acid, the profile of prostanoid synthesis was assessed by HPLC. Untransformed PGH2 released by the cells was evaluated as the difference in the formation of PGF2
in the incubations performed in
the presence and in the absence of SnCl2. Resting SMCs and
SMCs stimulated with phorbol 12-myristate 13-acetate (PMA),
lipopolysaccharide (LPS), interleukin (IL)-1ß, and tumor
necrosis factor (TNF)- formed PGE2 and PGI2
(evaluated as 6-oxo-PGF1), and in the presence of
SnCl2 only a small amount of PGE2 was deviated
toward PGF2. In contrast, resting and stimulated HUVECs
produced PGI2, PGE2, PGF2, and
PGD2, and SnCl2 completely diverted
PGE2 and PGD2 toward PGF2.
Reverse transcriptase–polymerase chain reaction analysis shows
that mRNA encoding for PGES was not present in HUVECs and in
endothelial cells from saphenous vein. Nevertheless,
PGES was expressed in SMCs and induced by IL-1ß and TNF-, and by
PMA and LPS, although to a lesser extent. Whereas SMC stimulation led
to an increase in the synthesis of PGE2 and
PGI2 but not of untransformed PGH2, stimulation
of endothelial cells resulted in an enhanced release of
the vasoconstricting prostanoid PGH2.
Key Words: prostaglandin E synthase • endothelium • smooth muscle • prostanoid • cytokine
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The potent relaxing and platelet antiaggregation agent prostaglandin (PG) I2 (also termed prostacyclin) is the characteristic prostanoid released by vascular endothelial1 and smooth muscle cells (SMCs).2 PGE2 is also a major prostanoid found to be produced in vitro by vascular cells in response to different agents, which include exogenously added arachidonic acid (AA) and several agonists.1 3 4 5 Cyclooxygenase (COX, also termed PGH synthase) is the first enzyme in the biosynthesis of prostanoids. Two COX isoforms have been described. COX-1 is expressed in a constitutive manner, whereas COX-2 is the isoenzyme inducible by mitogens and overexpressed in inflammatory processes.6 COX catalyzes the transformation of AA to PGH2, which has constricting and platelet-activating properties, because both thromboxane A2 and PGH2 share the same receptor.7 Prostacyclin synthase (PGI synthase; PGIS) catalyzes the subsequent transformation of PGH2 into PGI2. Isomerization of PGH2 to PGE2 may occur spontaneously8 or may be enzymatically catalyzed by a PGE synthase (PGES). The enzyme responsible for this isomerization was little known until the recent report by Jakobsson et al,9 who identified and characterized the human PGES as a membrane-bound enzyme of which the activity is glutathione-dependent and inducible by interleukin (IL)–1ß.
We reported that endothelial cells released untransformed PGH2 when COX activity increased and PGIS decreased as a result of the action of IL-1ß.5 10 Although endothelial cells produced PGE2 as a major prostanoid, in particular after cytokine stimulation, on the basis of indirect evidence we postulated that endothelial cells possess only 3 enzymes involved in the biosynthesis of prostanoids COX-1, COX-2, and PGIS.5 Because expression of PGES could not only modulate synthesis of PGE2 but could also modulate the release of untransformed PGH2 or even PGI2 by diverting metabolism of PGH2, this study was conducted to investigate the expression of PGES on vascular cells and its modulation by mitogens and cytokines.
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Materials and Methods |
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Cell Culture and Treatment
Human umbilical vein endothelial cells (HUVECs) were cultured as previously described.11 HUVECs in first passage were maintained without heparin and endothelial cell growth factor for 48 hours before the addition (or not) of 10 nmol/L phorbol 12-myristate 13-acetate (PMA, Sigma), 10 U/mL human recombinant IL-1ß (Boehringer Mannheim), 20 ng/mL recombinant human tumor necrosis factor (TNF)-
(Promega), or 100
µg/mL of lipopolysaccharide (LPS, Escherichia coli
serotype 0111:B4, Sigma) in M199 containing 1% FBS and maintained for
6 hours until incubation with [14C]AA or mRNA
extraction. Saphenous vein endothelial cells (SVECs)
were obtained by treatment of the endothelial surface
with a solution of collagenase (0.07% wt/vol) for 15
minutes. SVECs were scraped carefully, cultured, and treated as
described for HUVECs. SVECs were used in second passage.
Human dermal fibroblasts were isolated and cultured as
described.12 Cells in passages 4 to 6 were maintained with
1% FBS for 48 hours before treatment with PMA, IL-1ß, TNF-, or
LPS as described above.
SMCs were isolated from human popliteal artery by an explant procedure.
The artery was split longitudinally, and the
endothelium was removed by gently scraping. The tissue
was minced and seeded onto the culture surface in a small volume of
DMEM containing 10% FBS. SMCs were characterized by
-actin–positive staining. Cells in passages 4 to 7 were maintained
with 1% FBS for 48 hours before treatment with PMA, IL-1ß, TNF-,
or LPS as described above.
Determination of AA Metabolism in the Presence or
Absence of SnCl2
After treatment with the stimuli, cells were incubated in the
presence of 25 µmol/L [14C]AA (55 to 58
mCi/mmol, Amersham) as described.5 To estimate the
untransformed PGH2 released, we calculated the
difference between the PGF2 peak of the
samples from cells incubated as aforementioned and cells incubated in
the presence of 200 µg/mL SnCl2 as
described.5 Prostanoids were analyzed by HPLC as
described.13
Expression of PGES
After cell treatment with the stimuli, total RNA was isolated
and reverse-transcribed into cDNA and then subjected to a polymerase
chain reaction (PCR) protocol as previously described for COX-1 and
COX-2.12 Serial half-dilutions of the cDNA were performed
to test linearity. Specific primers (Progenetic SL) for PCR based on
the open reading frame of the microsomal glutathione-dependent
PGES sequence described9 were synthesized. The sequence of
the sense and antisense primers for human PGES were
5'-CTCTGCA-GCACGCTGCTGG-3' (sense) and
5'-GTAGGTCACGGAG-CGGATGG-3' (antisense).
This primer pair yielded an amplified product of the expected size
of 344 bp. After an initial denaturation for 5 minutes at 94°C, 27
cycles of amplification (94°C for 45 seconds, 65°C for 45 seconds,
and 72°C for 45 seconds) were performed, followed by a 10-minute
extension at 72°C, for all the samples. The amplification
products were separated by electrophoresis, and the radioactivity
associated with the specific band was evaluated and normalized to GAPDH
as previously described.12
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Prostanoid synthesis by SMCs was characterized by the formation of PGE2 and PGI2 (evaluated as 6-oxo-PGF1
); PGF2 was
not detected in the absence of SnCl2. When
SnCl2 was present in the incubation mixture,
only a small amount of PGE2 was deviated toward
PGF2, whereas formation of
PGI2 was not modified by
SnCl2. For comparative purposes human dermal
fibroblasts were included in the study, their prostanoid profile being
similar to that of SMCs (Figure 1
). PMA,
LPS, IL-1ß, and TNF- significantly increased the formation of
PGE2 in SMCs (Table).
Formation of PGI2 was significantly
increased only by PMA, IL-1ß, and TNF-.
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As expected, resting and treated HUVECs incubated with
[14C]AA produced PGI2
(evaluated as 6-oxo-PGF1),
PGE2, PGF2, and
PGD2 as prostanoids. Cell treatment with the
stimuli caused an increased production of prostanoids in
HUVECs. Nevertheless, the net effect of PMA, IL-1ß, TNF-, and LPS
on each particular prostanoid was not uniform (Table
).
PGE2 and PGD2 were the main
prostanoids increased by all of the inductors (Table). The
formation of PGI2 was only minimally modified by
the presence of SnCl2 in the medium. In contrast,
PGE2 and PGD2 completely
disappeared in the samples containing SnCl2, and
the levels of PGF2 increased concomitantly
(Figure 1).
Reverse transcriptase (RT)–PCR analysis of mRNA encoding for
PGES showed that the enzyme was expressed in SMCs and dermal
fibroblasts but not in HUVECs and in SVECs. PGES was strongly induced
by IL-1ß and TNF-, with IL-1ß being the most potent (Figure 2). PMA and LPS also significantly
induced PGES but to a lesser extent. Twenty-seven cycles of PCR were
usually performed for linearity, although no band corresponding to PGES
was detected in HUVECs and SVECs even after 35 cycles of PCR (not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present results clearly indicate that endothelial cells from fetal and adult vessels did not express PGES even after treatment with the cytokines, PMA, or LPS. It is well known that culture conditions influence AA metabolism in endothelial cells. It has been reported that COX is downregulated by endothelial cell growth factor and heparin.14 15 16 17 18 Under our experimental conditions, endothelial cells were maintained without heparin and endothelial cell growth factor for 48 hours before the addition (or not) of PMA, IL-1ß, TNF-
, or LPS to maximize prostanoid formation. An even more
important factor that regulates AA metabolism in cultured
endothelial cells is the number of subcultivations. It
has been reported that subcultivation negatively influences
PGI2 formation by endothelial
cells.19 20 Indeed, we also observed that HUVECs lose
their ability to form PGI2 as the number of
passages increase. The loss of activities of both COX and PGIS
was related to a diminution of the expression of COX-1 and PGIS, with
the loss of PGIS being faster than that of COX-1 in terms of mRNA
(unpublished results). The present results were obtained from
experiments performed with HUVECs and SVECs at first and second
passage, respectively, to maximize COX and PGIS activities and to
prevent the hypothetical loss of PGES expression with the number of
passages.
In contrast, PGES was expressed in resting and stimulated SMCs and
dermal fibroblasts. Consistently with the report of Jakobsson
et al,9 PGES was inducible by IL-1ß in SMCs and
fibroblasts but also by TNF-, PMA, and LPS, which indicated that it
is probably induced under inflammatory conditions. Our results are also
consistent with previous reports that
PGE2 is the most commonly induced
prostanoid by IL-1ß in SMCs, although in these works PGES expression
was not analyzed.21 22 Matsumoto et
al23 observed that LPS induced COX-2 expression and
enhanced PGES activity in rat macrophages. The fact that not
only PGE2 but also PGI2 was
increased by PMA, IL-1ß, and TNF- in SMCs was due to the induction
of COX-2 (evaluated by RT-PCR and Western blotting [not shown]) by
these agents, which indicates that formation of
PGI2 in SMCs is limited by COX activity rather
than by PGIS.
PGIS and PGES compete for the substrate because both PGIS and PGES have the same substrate (PGH2) and, like COX, both are located in the microsomal fraction. On the other hand, whereas PGES is an inducible enzyme,9 PGIS is not.5 The substrate distribution between PGIS and PGES is primarily governed by the relative affinity each enzyme has for the substrate. Experiments performed with preparations of purified bovine PGIS showed a Km of 7.3 to 9 µmol/L.24 25 Km values for PGES purified from rat tissues were between 25.5 and 82.6 µmol/L,26 and when purified from sheep vesicular glands, the Km value was 40 µmol/L.27 Unfortunately, there are still no data in the literature about the kinetic parameters of the human enzymes or even kinetic studies performed with PGIS and PGES preparations of the same species. In any case, theoretically, a modification in the proportion of PGIS and PGES molecules would probably influence the relative amount of PGI2 and PGE2 formed in a particular cell that expresses both enzymes. Hence, the induction of PGES could indirectly influence PGI2 formation. Results from experiments incubating cells with labeled AA showed a PGE2/PGI2 ratio of 1.8±0.2 and 2.2±0.5 (mean±SD, n=6) in controls and in IL-1ß–treated SMCs, respectively. This variation was in fact less apparent than expected. This could be due to the fact that other factors such as a different velocity of suicide inactivation of the PGIS and PGES and the total COX activity could also influence the relative amount of PGI2 and PGE2 formed under a particular condition.
More apparent was the effect of PGES expression on the release of untransformed PGH2, which has activity opposite that of PGI2. Although COX-2 was induced (not shown), treatment of SMCs with IL-1ß resulted in a significant decrease in their ability to release untransformed PGH2, which was likely a result of a concomitant induction of PGES. In contrast, COX-2 induction in HUVECs resulted in an enhanced ability to release the vasoconstricting prostanoid PGH2.5 The present results suggest that SMCs do not contribute to the release of PGH2 even under inflammatory conditions and reinforce the concept that release of PGH2 by vascular endothelial cells is exclusively regulated by the ratio of COX to PGIS activity.5 10 More research is needed to ascertain PGES expression under pathological conditions and in other endothelial cell phenotypes such as capillary endothelial cells.
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Acknowledgments |
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This work was supported by grants from Institut de Recerca of the Hospital Santa Creu i Sant Pau and from SAF96-0138. We thank Dr Manuel Fresno for his critical reading of the manuscript and Cristina and Esther Gerbolés for their technical assistance.
Received May 17, 2000; revision received July 10, 2000; accepted July 31, 2000.
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