© 2000 American Heart Association, Inc.
Cellular Biology |
Fluid Shear Stress Induces Lipocalin-Type Prostaglandin D2 Synthase Expression in Vascular Endothelial Cells
From the Departments of Bioscience (Y.T., T.S., M. Miyagi, Y.M.) and Epidemiology (T.A.), National Cardiovascular Center Research Institute, Osaka; Third Department of Internal Medicine (Y.T., M. Miyagi), University of the Ryukyus School of Medicine, Okinawa; and Department of Pathology (T.I., M. Mitsumata), School of Medicine, Yamanashi Medical University, Yamanashi, Japan.
Correspondence to Toshiyuki Sasaguri, MD, PhD, Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail sasaguri{at}ri.ncvc.go.jp
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Abstract—Ligands for peroxisome proliferator–activated receptor
, such as the
thiazolidinedione class of antidiabetic drugs and
15-deoxy-
12,14-prostaglandin J2
(15d-PGJ2), modulate various processes in atherogenesis. In
search of cells that generate prostaglandin D2
(PGD2), the metabolic precursor of
15d-PGJ2, we identified PGD2 from culture
medium of endothelial cells. To study how
PGD2 production is regulated in
endothelial cells, we investigated the role of fluid
shear stress in the metabolism of PGD2.
Endothelial cells expressed the mRNA for the
lipocalin-type PGD2 synthase (L-PGDS) both in vitro and in
vivo. Loading laminar shear stress using a parallel-plate flow chamber
markedly enhanced the gene expression of L-PGDS, with the maximal
effect being obtained at 15 to 30 dyne/cm2. The expression
began to increase within 6 hours after loading shear stress and reached
the maximal level at 18 to 24 hours. In contrast, shear stress did not
alter the expression levels of PGI2 synthase and
thromboxane A2 synthase. In parallel with the
increase in the expression level of L-PGDS, endothelial
cells released PGD2 and 15d-PGJ2 into culture
medium. These results demonstrate that shear stress promotes
PGD2 production by stimulating L-PGDS expression
and suggest the possibility that a peroxisome
proliferator–activated receptor ligand is produced in
vascular wall in response to blood flow.
Key Words: shear stress • vascular endothelial cells • prostaglandins
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Introduction |
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Prostaglandins (PGs) of the J2 family, including PGJ2,
12-PGJ2, and
15-deoxy-12,14-PGJ2
(15d-PGJ2), are the metabolites of
PGD2.1 2 These cyclopentenone PGs
were known as antitumor and antiviral PGs,3 before they
were revealed to be naturally occurring ligands for peroxisome
proliferator–activated receptor (PPAR), one of the
ligand-activated nuclear receptor transcription
factors.4 5 Among these PGs,
15d-PGJ2 is the most effective
activator for PPAR.
PPAR ligands have been shown to modulate multiple processes in
atherogenesis since they were found to promote the differentiation of
macrophages, increasing oxidized LDL uptake by stimulating the
expression of a scavenger receptor CD36.6 7 They also
inhibit inflammatory cytokine production in
monocytes.8 In vascular smooth muscle cells (VSMCs), they
prevent migration by inhibiting the expression of matrix
metalloproteinase-9.9 We reported that
PGJ2 and
12-PGJ2 strongly inhibit
proliferation of VSMCs,10 and we recently found that
15d-PGJ2 not only arrests the cell cycle but also
promotes the differentiation of VSMCs, inducing smooth muscle–specific
myosin heavy chains.11 PPAR ligands also have been
shown to inhibit angiogenesis in vitro and in vivo.12
PGs of the J2 family can be naturally generated from PGD2 in the presence of albumin.1 2 Although we have detected PGD2 from the culture medium of vascular endothelial cells in a preliminary study,13 it is uncertain that PGD2 is physiologically produced in the vascular wall. We therefore investigated whether endothelial cells express PGD2 synthase (PGDS) to produce PGD2 and, as a consequence, 15d-PGJ2. In this study, we particularly focused on the role of fluid shear stress, because blood flow is one of the crucial factors that regulate endothelial cell function, and its turbulence may promote atherosclerosis by disturbing homeostasis in vascular wall maintained by endothelial cells.14
Here we report for the first time that steady laminar shear stress stimulates endothelial cells to produce PGD2 and 15d-PGJ2 by upregulating the expression of PGDS.
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Materials and Methods |
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Chemicals
PGs were purchased from Cayman Chemical Co. Phorbol 12-myristate 13-acetate (PMA) was from Sigma Chemical Co.
Cell Culture
Vascular endothelial cells, VSMCs, and blood
monocytes were isolated and cultured as
described.15 16 17
Shear Stress Apparatus
Steady laminar shear stress was loaded on
endothelial cells grown on a gelatin-coated polyester
sheet (Plastic Suppliers) in a parallel-plate flow chamber as
described.18
Chromatography of Arachidonic
Acid Metabolites
Confluent cells were incubated in medium containing 9.25 kBq/mL
[14C]arachidonic acid (Amersham
Pharmacia Biotech) at 37°C. After 3 hours, the conditioned medium was
collected and acidified to pH 3.0 by adding HCl. Four times the volume
of ethyl acetate was then added, and the mixture was
centrifuged at 1000g for 10 minutes at 4°C. The
upper phase was collected and evaporated under nitrogen. After
dissolving with methyl acetate, samples were applied to a silica-gel
thin-layer chromatography (TLC) plate (silica gel 60
HPTLC, Merck), which was developed with chloroform/ethyl
acetate/ethanol/acetic acid (20:20:4:1, vol/vol). The plate was
analyzed for radioactivity with a bioimage analyzer
(BAS-2500, Fuji Photo Film Co) or exposed to an x-ray film at -80°C.
Radioactive spots were scraped off and re-extracted with ethanol. The
extracts mixed with standard PGs were applied to a Cosmosil 5C18 column
(Nacalai Tesque) using an HPLC system (Waters) and were eluted with
17 mmol/L
H3PO4/CH3CN
(7:3, vol/vol). The elution fractions were counted for radioactivity
with a scintillation counter (LS5801, Beckman Instruments). Standard
PGs were detected at a wavelength of 192.5 nm.
Enzyme Immunoassay (EIA)
One milliliter of culture medium was acidified to pH 3.0 by
adding HCl and applied to an Amprep C2 minicolumn (Amersham Pharmacia
Biotech). After a wash with water, 10% ethanol, and hexane, PGs were
eluted with methyl formate. Next, the eluent was evaporated, and
residues were dissolved in the assay buffer included in the EIA kits
for PGD2 and 15d-PGJ2
(Cayman Chemical Co). The concentrations of PGs were determined using
these kits according to the manufacturer’s protocol and using a
microplate reader (ImmunoMini NJ-2300, Nalge Nunc International).
Reverse Transcription–Polymerase Chain Reaction (RT-PCR)
RT-PCR was performed as described,19 using PCR
primers synthesized on the basis of the GenBank database.
Northern Blotting
Northern blotting was performed as described,16
using cDNAs cloned by RT-PCR.
In Situ Hybridization
The riboprobe was synthesized from a template cDNA fragment in
the presence of digoxigenin-UTP (DIG) and T3 RNA polymerase (Promega)
for antisense or T7 RNA polymerase (Promega) for sense, using a DIG RNA
labeling kit (Roche Diagnostics). Fresh autopsy specimens
were fixed with 4% paraformaldehyde in PBS overnight
at 4°C. Hybridization was carried out by incubating the sections with
a denatured DIG-labeled antisense or sense riboprobe (1 µg/mL) in a
moist chamber for 16 hours at 42°C. After RNase treatment, the
sections were incubated with an anti-DIG antibody conjugated with
alkaline phosphatase. Hybridized probes were detected by revealing
phosphatase activity with 4-nitroblue tetrazolium chloride and
5-bromo-4-chloro-3-indolyl phosphate.
Immunohistochemistry
Immunostaining was performed as previously
described.20
Statistics
Results are expressed as mean±SD. Statistical significance was
assessed by Student t test.
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Results |
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Detection of PGD2 in Endothelial Cell Culture Medium
In search of vascular cells that are able to produce PGD2, we analyzed arachidonic acid metabolites of VSMCs, endothelial cells, and monocytes. The cells were incubated with [14C]arachidonic acid for 3 hours in the absence or presence of PMA, and then the metabolites contained in the culture media were analyzed by TLC (Figure 1A
). The most abundant
product in VSMCs seemed to be PGE2, but there
was no band that corresponded with the authentic standard of
PGD2. In endothelial cells, a
weak band corresponding with PGD2 was found, and
its level was elevated in the presence of PMA. Metabolites re-extracted
from this band were analyzed by HPLC (Figure 1B). A
radioactive peak consistent with authentic
PGD2 was found in the extract. In monocytes,
relatively strong bands were found close to authentic
PGD2 (Figure 1A). However, HPLC
analysis revealed that they were not
PGD2, given that no radioactivity was found in
the fractions in which authentic PGD2 was eluted
(not shown).
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,
monocytes/macrophages. B, TLC band corresponding with
PGD2 (arrowhead) was re-extracted and analyzed by
HPLC. Arrow indicates position where an authentic standard
PGD2 was eluted.
Shear Stress Stimulates the Production of PGD2
and 15d-PGJ2 in Endothelial Cells
Although we detected PGD2 in culture medium
of endothelial cells, the amount of the PG produced
under static conditions seemed to be small. Considering that the
synthesis of PGI2 is upregulated by fluid shear
stress,21 we wondered whether shear stress also stimulates
PGD2 production. After exposing
endothelial cells to shear stress (15
dyne/cm2) for 24 hours, we incubated the cells in
fresh medium with
[14C]arachidonic acid under
static conditions for a further 3 hours and analyzed the PGs
released into the medium by TLC (Figure 2). The amount of
PGD2 released from the cells pre-exposed to shear
stress was 
3 times that generated by the control cells.
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PGD2 released into culture medium was quantified
by EIA. After exposing endothelial cells to shear
stress (15 dyne/cm2) for 24 hours, the cells were
cultured in fresh medium under static conditions for various times, and
the concentrations of PGD2 were determined
(Figure 3A). In cells pre-exposed to
shear stress, the concentration of PGD2 increased
linearly until 3 hours had passed. Therefore, to evaluate the activity
of cells to synthesize PGD2, we exposed cells to
shear stress (15 dyne/cm2) for various periods
and measured the amount of PGD2 synthesized
during the next 3 hours under static conditions (Figure 3B). In
sheared cells, the level of PGD2 began to
increase within 6 hours and achieved a plateau in 18 to 24 hours. In
contrast, the level was not significantly changed in the static control
cells.
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, Static control (SC); •, shear stress (SS).
We then measured 15d-PGJ2 by EIA using the same
protocol as in Figure 3B
(Figure 3C). In sheared cells,
the level of 15d-PGJ2 also began to increase
within 6 hours, but it continued to increase until 24 hours without
reaching a plateau, whereas in controls, the increase was small and had
reached a plateau by 18 hours.
Shear Stress Induces L-PGDS Expression
To determine the mechanism for the accelerated production
of PGD2 in sheared cells, we examined the effect
of shear stress on the expression of PGDS, which mediates the isomeric
conversion of PGH2 to
PGD2.22 RNAs extracted from
endothelial cells were analyzed by RT-PCR
(Figure 4A). In static cells, the
expression level of the mRNA for the lipocalin-type PGDS (L-PGDS)
seemed to be very low. However, it was elevated by shear stress
depending on the time of loading of the stress. In parallel to the
increase in the amount of synthesized PGD2, the
level of L-PGDS mRNA began to increase within 6 hours and reached a
maximal level at 18 to 24 hours. However, the mRNA for the
hematopoietic-type PGDS (H-PGDS) was not detected in
endothelial cells even after exposure to shear
stress.
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To quantify the expression levels of L-PGDS, we performed Northern
blotting (Figures 4B and 4C). A 0.9-kb band, which has been
reported to be human L-PGDS mRNA,23 was clearly detected,
and an additional weak band was detected at 5 to 6 kb. The alterations
in their levels were in parallel. There was no increase in the mRNA
level when cells were cultured under static conditions. However, the
expression level in sheared cells was elevated from 6 hours, and it was
13 times as high as that in the static control cells at 24
hours.
The mRNAs for PGI2 synthase (PGIS) and
thromboxane A2 synthase (TXS) also
were expressed in endothelial cells (Figure 5). However, in contrast to L-PGDS
expression, their levels were not influenced by shear stress, although
PGIS expression tended to slightly increase 18 to 24 hours after a
change of medium.
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The shear stress–induced L-PGDS expression depended on the strength of
the stress (Figure 6). Shear stress of
relatively high strength (10 to 30 dyne/cm2)
markedly stimulated L-PGDS mRNA expression, with the maximal effect
being obtained at 15 to 30 dyne/cm2. However, the
increase in the level of the mRNA was small in cells cultured under
shear stress of lower strength (<5
dyne/cm2).
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L-PGDS Expression in Arterial
Endothelium In Vivo
Finally, we examined whether L-PGDS is expressed in
endothelial cells in vivo by in situ hybridization
(Figure 7). L-PGDS mRNA was clearly
detected in human aortic endothelial cells in all of
the autopsy cases studied. Cells in the intima, probably migrating
VSMCs, also expressed L-PGDS mRNA, whereas VSMCs in the media were not
stained.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We found that vascular endothelial cells express L-PGDS mRNA in vitro and in vivo and that shear stress stimulates its expression in vitro, thereby stimulating the production of PGD2 and 15d-PGJ2. These results indicated the possibility that a PPAR
ligand is produced in
vascular wall in response to mechanical stimuli generated by blood
flow. Enzymes that catalyze the isomeric conversion of PGH2 to PGD2 are classified into 2 species, namely L-PGDS and H-PGDS.22 Although these 2 enzymes catalyze the same reaction, they have no homology in amino acid sequence.23 24 L-PGDS found to be expressed in endothelial cells had been known as ß-trace, a 26-kDa protein that is a major soluble component of cerebrospinal fluid, before it was revealed to function as a PGDS.25 In the meantime, L-PGDS belongs to the lipocalin superfamily that includes various secretory lipid-transporter proteins,22 and therefore, it could operate as a carrier protein for small lipophilic molecules. However, the expression of H-PGDS, which is a glutathione-requiring enzyme mainly expressed in antigen-presenting cells, mast cells, and megakalyoblasts,22 was not detected in endothelial cells.
In the central nervous system, PGD2 produced by L-PGDS has been suggested to regulate the sleep-awakening cycle.22 Recently, L-PGDS was found in human serum at a concentration of 0.2 to 0.4 µg/mL, and its level in coronary circulation was elevated in patients with ischemic heart disease.26 L-PGDS was expressed in cardiomyocytes, atrial endocardial cells, and VSMCs in the atherosclerotic intima.26 However, our study suggests that endothelial cells may be a major source of L-PGDS and PGD2 contained in serum.
The factors controlling L-PGDS gene expression are poorly identified except for thyroid hormone receptor. The expression level of L-PGDS mRNA decreases in hypothyroid rat brain.27 Recently it has been revealed that the complex of T3 and thyroid hormone receptor-ß elevates the L-PGDS promoter activity by binding to a thyroid hormone response element.28 29 Further studies are needed to identify the transcription factors involved in the L-PGDS expression in response to shear stress.
The manner in which shear stress regulates PGD2 synthesis seemed to be different from that for PGI2. Shear stress markedly upregulated L-PGDS expression, whereas there was no difference in the expression levels of PGIS between the sheared and static cells, despite the fact that shear stress stimulates the release of PGI2 from endothelial cells.21 Shear stress activates enzymes involved in arachidonic acid metabolism, such as phospholipase C,30 31 diacylglycerol lipase,30 and cytosolic phospholipase A2,32 and it also stimulates the expression of cyclooxygenase-2.33 Therefore, shear stress may stimulate the common pathway for PG synthesis beginning with the liberation of arachidonic acid and ending with the synthesis of PGH2; however, its downstream may be diversely regulated. L-PGDS activity is upregulated by increasing its expression, whereas PGIS is activated by post-translational modification but not by elevating its expression. The possibility remains that L-PGDS activity also is regulated by protein modification.
It is of clinical interest that L-PGDS is accumulated in
coronary circulation of angina patients.26 At this
stage, however, it is not clear whether this is a protective response
against ischemia or an undesirable factor for patients.
PGD2 reportedly prevents platelet aggregation
through activation of adenylate cyclase34 and
induces endothelium-dependent arterial
relaxation.35 Its metabolites, the
J2 family PGs, display various effects on the
process of atherogenesis, as mentioned previously. Most of their
effects appear to be preventive for the formation of atherosclerotic
lesions and to be beneficial for stabilizing the plaques. However,
these PGs could be proatherogenic, first because it is undetermined
whether the PPAR ligand–induced differentiation of
macrophages is antiatherogenic or
proatherogenic.6 7 Secondly,
15d-PGJ2 has been reported to induce
endothelial cell apoptosis.36
However, a completely opposite result has been obtained in our study,
namely that 15d-PGJ2 inhibited
endothelial cell apoptosis (Y. Taba et al,
unpublished data, 1999).
Considering that the formation of atherosclerotic lesions is less frequent in the areas exposed to laminar and high shear stress,18 it is important to study whether PGs produced by L-PGDS contribute to the shear stress–mediated prevention of atherosclerosis. As far as our in vitro experiments are concerned, laminar shear stress–induced L-PGDS mRNA expression depends on the strength of the stress. Under high shear stress (15 to 30 dyne/cm2) corresponding to the stress in arteries, L-PGDS expression was markedly stimulated, whereas under low shear stress (<5 dyne/cm2) corresponding to that in veins, the stimulation was weak. We examined whether the in vivo expression levels of L-PGDS are different among the areas of human aortas and their major branches where the strength of shear stress is supposed to be different. However, endothelial cells ubiquitously expressed L-PGDS mRNA without significant difference in the expression levels among the areas (not shown). It should be further investigated whether changes in the pattern of blood flow, such as turbulence, influence the expression level and activity of this enzyme.
Intimal cells, which were probably VSMCs, exhibited L-PGDS signals in all of the autopsy cases studied, despite the fact that we did not detect PGD2 in the culture medium of VSMCs. RT-PCR revealed that cultured VSMCs expressed only a trace of L-PGDS mRNA (not shown). Therefore, the amount of PGD2 produced in cultured cells may have been too small to be detected by TLC, which is not a very sensitive method. The reason why intimal cells clearly expressed L-PGDS mRNA is unclear. They may be activated under in vivo conditions by unknown stimuli derived from surrounding cells to induce L-PGDS expression.
We hypothesize that laminar shear stress stimulates the production of PGD2 and 15d-PGJ2 by upregulating the expression of L-PGDS in endothelial cells and consequently prevents the development of atherosclerotic lesions.
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Acknowledgments |
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This study was supported in part by grants from the Ministry of Health and Welfare (Research Grants for Cardiovascular Diseases 9A-4 and 11C-1); Ministry of Education, Science, and Culture (a Grant-in-Aid for Scientific Research); Science and Technology Agency (Special Coordination Funds for Promoting Science and Technology [Encouragement System of Center of Excellence]); Japan Cardiovascular Research Foundation; and Sankyo Foundation of Life Science.
Received November 29, 1999; accepted March 20, 2000.
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