Fluid Shear Stress Transcriptionally Induces Lectin-like
Oxidized LDL Receptor-1 in Vascular Endothelial Cells
Takatoshi Murase, Noriaki Kume, Risa Korenaga, Joji Ando, Tatsuya Sawamura,
Tomoh Masaki, Toru Kita
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Abstract—Fluid shear stress has been shown to modulate various endothelial functions, including gene expression. In this
study, we examined the effect of fluid shear stress on the expression of lectin-like oxidized LDL receptor-1 (LOX-1),
a novel receptor for atherogenic oxidized LDL in cultured bovine aortic endothelial cells (BAECs). Exposure of BAECs
to the physiological range of shear stress (1 to 15 dyne/cm2) upregulated LOX-1 protein and mRNA in a time-dependent
fashion. LOX-1 mRNA levels peaked at 4 hours, and LOX-1 protein levels peaked at 8 hours. Inhibition of de novo
RNA synthesis by actinomycin D totally abolished shear stress–induced LOX-1 mRNA expression. Furthermore,
nuclear runoff assay showed that shear stress directly stimulates transcription of the LOX-1 gene. Chelation of
intracellular Ca21 with quin 2-AM completely reduced shear stress–induced LOX-1 mRNA expression; furthermore, the
treatment of BAECs with ionomycin upregulated LOX-1 mRNA levels in a dose-dependent manner. Taken together,
physiological levels of fluid shear stress can regulate LOX-1 expression by a mechanism dependent on intracellular Ca21
mobilization. Inducible expression of LOX-1 by fluid mechanics may play a role in localized expression of LOX-1 and
atherosclerotic lesion formation in vivo. (Circ Res. 1998;83:328-333.)
Key Words: atherosclerosis n oxidized LDL n fluid shear stress n intracellular Ca21 n C-type lectin
E
modulation of endothelial functions elicited by Ox-LDL and its
lipid constituents has been implicated in the initiation of this
complex disease process.36,37 We have recently identified a novel
endothelial receptor for Ox-LDL, designated lectin-like Ox-LDL
receptor-1 (LOX-1), whose structure belongs to the C-type lectin
family.38 LOX-1 is expressed in vascular endothelium in vivo in
arterial and aortic endothelial cells, including atherosclerotic
lesions.38 Functional analysis revealed that LOX-1 expressed on
the surface of endothelial cells supports binding, internalization,
and proteolytic degradation of Ox-LDL. With regard to transcriptional regulation of LOX-1, an inflammatory stimulus, such
as tumor necrosis factor-a, appears to stimulate transcription of
the LOX-1 gene.38a LOX-1 expression in vivo also has been
shown to be upregulated in the aortas and veins of hypertensive
rats.39 Therefore, we have tested the hypothesis that expression
of LOX-1 can be modulated by fluid mechanical stimuli in
vascular endothelial cells.
In the present study, we provide evidence that fluid shear
stress is a potent stimulus to transcriptionally induce the expression of LOX-1 in cultured bovine aortic endothelial cells
(BAECs).
ndothelial cells lining the inner surface of vessel walls are in
direct contact with blood flow, which generates a hemodynamic shear stress acting on the apical surface of vascular
endothelium.1,2 Fluid shear stress has been shown to modulate a
variety of endothelial functions, including the expression of a
variety of genes, such as endothelin-1,3–5 cyclooxygenase-2,6 NO
synthase,6,7 tissue factor,8 transforming growth factor-b,9 platelet-derived growth factor (PDGF),10,11 basic fibroblast growth
factor,11 heparin-binding epidermal growth factor–like growth
factor,12 monocyte chemotactic protein-1,13 intercellular adhesion molecule-1,14,15 and vascular cell adhesion molecule-1,16,17
as well as its effects on cytoskeletal organization and cell
morphology.4,18,19 These biological effects elicited by fluid shear
stress appear to be mediated by intracellular signal transduction
cascades, including intracellular Ca21 mobilization,20–22 inositol
trisphosphate,23 K1 channel,24 G protein,25 mitogen-activated
protein kinases,26,27 N-terminal Jun kinase,28,29 and platelet endothelial cell adhesion molecule-1 tyrosine phosphorylation,30 and
by the subsequent activation of transcription factors, such as
activator protein-1 (AP-1),31,32 nuclear factor-kB (NF-kB),31,33
and Egr-1 (an early growth response gene product),34,35 and may
potentially affect vascular tone, thrombus formation, and
atherogenesis.1,36
On the other hand, oxidatively modified LDL (Ox-LDL) has
been suggested to play key roles in atherogenesis. In particular,
Materials and Methods
Reagents
DMEM was obtained from Nissui. FCS was obtained from Boehringer Mannheim. [32P]UTP, the Gene Image DNA labeling and
Received March 5, 1998; accepted June 16, 1998.
From the Departments of Geriatric Medicine and Pharmacology (T.M., N.K., T.S., T.M., T.K.), Graduate School of Medicine, Kyoto University, Kyoto,
Japan, and the Department of Biomedical Engineering (R.K., J.A.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan. The present address
for Dr Murase is Biological Science Laboratories, Kao Corp, Ichikaimachi, Tochigi, Japan.
Correspondence to Noriaki Kume, MD, PhD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho,
Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail [email protected]
© 1998 American Heart Association, Inc.
328
Murase et al
detection system, ECL Western blotting detection reagents, and
Hybond-N1 membranes were obtained from Amersham. Quin
2-AM, Isogen, and Isogen-LS were from Wako Pure Chemical.
PVDF transfer membranes were obtained from Millipore.
Cell Culture
BAECs were isolated by scraping the inner surface of bovine aortas
with a glass coverslip and cultured in DMEM containing 10%
heat-inactivated FCS in an atmosphere of 95% air/5% CO2 at 37°C
as previously described.38 For shear experiments, BAECs were
seeded on collagen-coated glass slides (703100 mm) in DMEM with
10% FCS. Before experiments, BAECs on the glass slides were
incubated with serum-free DMEM for 24 hours.
Shear Stress Apparatus
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A parallel-plate type of flow chamber was used to produce laminar
flow as previously described.15–17,20 In brief, BAECs were cultured on
glass plates and loaded into a rectangular parallel-plate flow chamber. Shear stress was increased suddenly from 0 (static) to 15
dyne/cm2 (or the indicated intensities of shear stress) and was
maintained at the same level for the time periods indicated for each
experiment. Culture media were recirculated into the chamber and
kept at a constant temperature of 37°C with a gas mixture of 95%
air/5% CO2.
Northern Blot Analysis
BAECs were washed in PBS, and total RNA was isolated using
Isogen. Equal amounts (10 mg) of total RNA were subjected to
electrophoresis through 1% agarose/formamide gels and blotted onto
Hybond-N1 membranes. Hybridization and detection were performed by fluorescein-labeled cDNA using the Gene Image random
prime labeling and detection system (Amersham) according to the
manufacturer’s instructions. In brief, the blots were prehybridized for
6 hours at 65°C in a solution containing 5% (wt/vol) dextran sulfate,
53 SSC, 0.1% (wt/vol) SDS, and blocking reagent and subsequently
hybridized with a fluorescein-labeled cDNA probe at 65°C overnight. The membranes were washed with 13 SSC and 0.1% (wt/vol)
SDS for 15 minutes and then washed with 0.13 SSC and 0.1%
(wt/vol) SDS for 15 minutes at 65°C. After nonspecific binding of
antibodies was blocked, the membranes were incubated with alkaline
phosphatase–labeled anti-fluorescein antibody for 1 hour and then
detected by chemiluminescence (CDP-star reagent, Amersham).
Densitometric scanning was performed to quantify the amounts of
mRNA using NIH Image. Amounts of LOX-1 mRNA were normalized with the amounts of GAPDH mRNA.
Western Blot Analysis
BAECs were washed in PBS and lysed in buffer containing
62.5 mmol/L Tris-HCl, 2% (wt/vol) SDS, and 10% (vol/vol) glycerol. Equal protein concentrations of the lysates were subjected to
SDS-polyacrylamide (10%) gel electrophoresis, followed by electroblotting onto an Immobilon PVDF transfer membrane. Determination of protein concentrations was carried out by the method of
Lowry. Blotted membranes were probed with a mouse monoclonal
antibody directed to bovine LOX-1,38 incubated with horseradish
peroxidase–labeled-anti-mouse immunoglobulin for 1 hour, washed
with PBS containing 0.1% (vol/vol) Tween 20, and then detected by
ECL Western blotting detection reagents. Densitometric scanning
was performed to quantify the amounts of LOX-1 protein using NIH
Image.
Nuclear Runoff Assay
Nuclear runoff assay was performed as previously described,40 with
minor modification. Briefly, the cells were washed with ice-cold
PBS and lysed with 0.5% Nonidet P-40 solution (10 mmol/L
Tris-HCl, 10 mmol/L NaCl, 3 mmol/L MgCl2, and 0.5% NP-40
[vol/vol], pH 7.4). The nuclei were isolated by centrifugation and
resuspended in a 40% glycerol buffer (50 mmol/L Tris-HCl, 40%
[vol/vol] glycerol, 5 mmol/L MgCl2, and 0.1 mmol/L EDTA, pH
8.3). Nascent transcription in vitro was performed with [32P]UTP and
August 10, 1998
329
other unlabeled nucleotides at 30°C for 30 minutes. Transcribed
RNA was isolated by Isogen-LS, followed by denaturation with
sodium hydroxide and ethanol precipitation. Linearized target
cDNAs (5 mg in plasmid form) were alkali-denatured and immobilized
onto Hybond-N1 membranes using a slot blot apparatus (Schleicher &
Shuell Inc). The membranes were hybridized with transcribed RNAs
containing an equal amount of radioactivity in a solution containing
50% (vol/vol) formamide, 53 SSPE (13 SSPE consists of 0.15 mol/L
NaCl, 10 mmol/L NaH2PO3, and 1 mmol/L EDTA, pH 7.4), 0.1%
(wt/vol) SDS, 10% (vol/vol) Denhardt’s solution, and denatured salmon
sperm DNA at 42°C for 36 hours. Filters were washed in 13 SSC with
0.1% (wt/vol) SDS for 15 minutes at room temperature, washed with
0.23 SSC supplemented with 0.1% (wt/vol) SDS for 10 minutes at
42°C, and then autoradiographed with Fujix Bioimage Analyzer
BAS2000 (Fuji Photo Film).
Results
Shear Stress Induces LOX-1 Expression in
Cultured Endothelial Cells
To test whether shear stress induces LOX-1 expression at the
protein level, confluent BAECs in a flow chamber were
subjected to a steady level of laminar shear stress of 15
dyne/cm2 for various periods of time. Time course of shear
stress–induced LOX-1 protein expression showed that elevated levels of LOX-1 protein were detectable within 4 hours
and reached to the maximal level at 8 hours in response to 15
dyne/cm2 of shear stress (Figure 1A). Densitometric analysis
showed that exposure to shear stress resulted in 2.4-fold,
3.7-fold, and 2.9-fold increases in the amounts of LOX-1
protein at 4, 8, and 12 hours, respectively, compared with the
levels in BAECs kept in a static condition. To determine
whether shear stress–induced expression of LOX-1 depends
on increased expression of LOX-1 mRNA, Northern blot
analyses were performed. As shown in Figure 1B, confluent
BAECs constitutively expressed modest levels of LOX-1
mRNA. Exposure of BAECs to 15 dyne/cm2 of shear stress
led to a rapid and transient increase in the amount of LOX-1
mRNA. The LOX-1 mRNA levels peaked at 4 hours (5.6-fold
increase) and were reduced after 8 hours.
To examine shear-force dependence in LOX-1 expression,
confluent BAECs were exposed to a broad range of shear
stresses (1 to 15 dyne/cm2) for 8 hours. These levels of shear
stress appear to be within the physiological range of shear
stress in vivo and have been shown to regulate a variety of
endothelial genes in vitro. As shown in Figure 2A and 2B,
shear stress force-dependently induced the expression of
LOX-1 protein; increased amounts of LOX-1 protein were
detectable in BAECs exposed to shear stress as low as 1 to 2
dyne/cm2. Elevated levels of LOX-1 mRNA were observed in
BAECs stimulated with shear stress as low as 2 dyne/cm2
(Figure 2C).
To explore whether continuous exposure to shear stress is
needed in induced expression of LOX-1, BAECs that had
been exposed to shear stress for the indicated time periods
were switched to a static condition for the residual time
periods. BAECs that were exposed to shear stress for an
initial 30 minutes and then cultured in a static condition
showed elevated levels of LOX-1 mRNA expression after 4
hours that were almost equal to those in BAECs exposed
continuously to shear stress for 4 hours (Figure 3). These
330
Shear Stress Induces LOX-1
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Figure 1. Time course of shear stress–induced LOX-1 expression. After BAECs cultured on glass slides were exposed to
shear stress (15 dyne/cm2) for the indicated time periods, immunoblot (A) and Northern blot (B) analyses were performed to
measure LOX-1 protein and mRNA levels. BAECs kept in a
static condition served as “time 0.” One of 2 independent
experiments is shown.
results indicate that the initial changes in fluid shear stress
may be crucial in the induced expression of LOX-1.
Shear Stress–Induced LOX-1 Expression Does Not
Require De Novo Protein Synthesis
To test whether de novo protein synthesis is necessary for the
shear stress–induced LOX-1 mRNA expression, cycloheximide was added to BAECs 1 hour before the application of
shear stress. The inhibition of the cellular protein synthesis by
cycloheximide was accompanied by increased basal LOX-1
levels, thought to be due to “superinduction,” and increased
LOX-1 mRNA levels in the static cells were the same as the
levels in cells subjected to shear stress of 15 dyne/cm2 (Figure
4). When cycloheximide-treated cells were subjected to shear
stress, levels for LOX-1 mRNA in these cells were again
higher than those in cycloheximide-treated cells. Taken
together, de novo protein synthesis is not necessary for shear
stress–induced LOX-1 gene expression, but protein synthesis
inhibition superinduced LOX-1 mRNA.
Shear Stress Stimulates Transcription of
LOX-1 Gene
To examine whether shear stress–induced expression of
LOX-1 depends on enhanced transcription of the LOX-1
Figure 2. Dependence on intensities of shear stress in LOX-1
expression. After BAECs were exposed to shear stresses of 1 to
5 dyne/cm2 (A) or 2 to 15 dyne/cm2 (B and C), LOX-1 protein
and mRNA levels were evaluated by immunoblot analyses (A
and B) and Northern blot analyses (C). A representative figure
from 2 independent experiments is shown.
gene, actinomycin D, an inhibitor of de novo mRNA synthesis, was added to BAECs 30 minutes before the application of
shear stress. Pretreatment with actinomycin D completely
abolished LOX-1 mRNA induction elicited by shear stress
(Figure 5). These results suggest that shear stress can stimulate transcription of the LOX-1 gene.
To obtain direct evidence that LOX-1 mRNA expression
was regulated at the transcriptional level, nuclear runoff
assays were performed with the use of nuclei isolated from
BAECs stimulated with or without fluid shear stress. Enhanced transcription of LOX-1 was observed in nuclear
extracts from shear stress–treated cells compared with those
kept in a static condition (Figure 6). Transcription of the
GAPDH gene, in contrast, was not significantly altered by
fluid shear stress. Thus, these results demonstrate that fluid
shear stress stimulates transcription of the LOX-1 gene.
Intracellular Ca21 Regulates Shear Stress–Induced
Expression of LOX-1
Fluid shear stress can rapidly elevate intracellular Ca21 levels;
this Ca21 elevation has been implicated in shear stress–
induced gene expression, such as induction of NO synthase7
and heparin-binding epidermal growth factor–like growth
factor.12 To determine whether shear stress–mediated increases in intracellular Ca21 were crucial for shear stress–
induced LOX-1 expression, effects of quin 2-AM, a chelator
Murase et al
August 10, 1998
331
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Figure 5. Dependence of LOX-1 gene induction on de novo
RNA synthesis. After pretreatment with or without actinomycin D
(2.5 or 5 mg/mL) for 30 minutes, BAECs were either subjected to
15 dyne/cm2 of shear stress or cultured in a static condition for
4 hours in the presence or absence of actinomycin D (2.5 or 5
mg/mL). Total RNA was isolated from BAECs, and Northern blot
analyses were performed. One of 2 similar experiments is
shown.
Figure 3. Effects of transient and continuous shear stress on
LOX-1 mRNA induction. BAECs grown to confluence on the culture slides were incubated at 15 dyne/cm2 of shear stress (3) or
a static condition (—-). LOX-1 mRNA levels were determined by
Northern blot analysis using a bovine LOX-1 cDNA probe.
Amounts of LOX-1 mRNA were measured by densitometry and
were normalized with the amounts of GAPDH mRNA. One of 2
similar experiments is shown.
of intracellular Ca21, were examined. Pretreatment of BAECs
with quin 2-AM (10 to 20 mmol/L) for 2 hours completely
inhibited shear stress–induced expression of LOX-1 mRNA
(Figure 7).
We also tested whether Ca21 mobilization alone is sufficient for LOX-1 induction in BAECs. Ionomycin, a Ca21
ionophore, markedly induced LOX-1 mRNA in a dosedependent manner (Figure 8). The LOX-1 mRNA level in
BAECs treated with 10 mmol/L of ionomycin for 4 hours was
Figure 4. Effect of cycloheximide on shear stress–induced
LOX-1 mRNA. After confluent BAECs were preincubated with or
without 50 mg/mL of cycloheximide for 30 minutes, cells were
then exposed to shear stress (15 dyne/cm2) or kept under a
static condition for 4 hours. Levels for LOX-1 mRNA were evaluated by Northern blot analyses. A representative result from 2
independent experiments is shown.
5.7 times higher than that in untreated BAECs. These results
indicate that shear stress–induced LOX-1 expression appears
to depend on intracellular Ca21 mobilization.
Discussion
Vascular endothelial cells are located as an interface between
the bloodstream and vessel wall cells. Endothelial functions
can be dynamically modulated in response to a variety of
pathophysiological stimuli, including mechanical forces. In
the present study, we have explored the possibility that
LOX-1, a novel endothelial receptor for Ox-LDL, is also a
shear stress–inducible molecule.
Inducible expression of LOX-1 by shear stress is demonstrated at both the protein and the mRNA levels in BAECs
(Figures 1 and 2). Furthermore, Northern blot analyses using
actinomycin D, as well as nuclear runoff assays, have
revealed that shear stress can stimulate transcription of the
LOX-1 gene (Figures 5 and 6). Induction of LOX-1 by fluid
shear stress was relatively transient; shear stress–induced
LOX-1 mRNA levels peaked at 4 hours and had decreased by
50% after 12 hours compared with the peak level. LOX-1
protein levels peaked at 8 hours and were reduced by 30%
after 12 hours. These time courses of LOX-1 expression
induced by shear stress are different from those observed with
tumor necrosis factor-a, which induced sustained levels of
LOX-1 expression (data not shown), suggesting that distinct
Figure 6. Shear stress stimulates transcription of LOX-1 gene.
BAECs were grown to confluence on the culture slides and
were either exposed to 15 dyne/cm2 of shear stress or kept in a
static condition for 2 hours. Nuclei were isolated from BAECs,
and transcriptional activities of the LOX-1 gene were assessed
by a nuclear runoff assay. Transcriptional activities for GAPDH
served as controls. One of 2 independent experiments is shown.
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Shear Stress Induces LOX-1
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Figure 7. Effects of intracellular Ca21 chelator quin 2-AM on
shear stress–induced LOX-1 mRNA expression. Confluent
BAECs were either preincubated with or without the indicated
concentrations of quin 2-AM for 2 hours at 37°C. After they
were washed, BAECs were subjected to 15 dyne/cm2 of shear
stress or kept in a static condition for 4 hours. Total RNA was
isolated from BAECs and subjected to Northern blot analysis. A
representative figure from 2 independent experiments is shown.
signal transduction pathways and transcriptional regulatory
mechanisms are involved.
Our studies involving the transient application of shear
stress in BAECs (Figure 3) show that initial stimulation with
shear stress is sufficient for induced expression of LOX-1 and
that sustained application of shear stress is not necessarily
required. This appears to suggest that early signal transduction events elicited by shear stress may play a crucial role in
LOX-1 induction. Therefore, we have focused on early events
in signal transduction pathways activated by shear stress.
Previous publications have shown that shear stress can
stimulate phosphatidylinositol turnover, generating inositol
1,4,5-trisphosphate and 1,2-diacylglycerol23 in cultured vascular endothelial cells. Inositol 1,4,5-trisphosphate can promote the rapid release of Ca21 from endoplasmic reticulum
and, thereby, raise the cytosolic free Ca21 levels. Thus, the
rapid increases in intracellular Ca21 levels elicited by shear
stress have been proposed as one of the earliest events in
Figure 8. Ionomycin enhances LOX-1 mRNA levels. Confluent
BAECs were exposed to the indicated concentrations of ionomycin for 4 hours at 37°C. Northern blot analyses were carried
out to measure LOX-1 mRNA levels. One of 2 similar results is
shown.
shear stress–induced signal transduction pathways in endothelial cells.20 –22 As we have shown in Figure 7, induction of
LOX-1 mRNA by shear stress was completely inhibited by
chelation of intracellular Ca21 with quin 2-AM. In addition,
ionomycin, which raises intracellular Ca21 levels, by itself
increased LOX-1 mRNA levels (Figure 8). Taken together,
elevated levels of intracellular Ca21 were necessary and
sufficient for LOX-1 gene expression elicited by shear stress.
On the other hand, 1,2-diacylglycerol, an activator of
protein kinase C (PKC), also appears to be responsible for a
variety of cellular responses. In fact, shear stress–induced
expression of certain genes, such as PDGF,10 heparin-binding
epidermal growth factor–like growth factor,12 and c-fos,41
were shown to be mediated by PKC activation. Although both
Ca21 mobilization and PKC activation have been shown to be
induced by fluid shear stress, our preliminary studies have
shown that GF109203X, a specific inhibitor of PKC, failed to
inhibit shear stress–induced LOX-1 expression (data not
shown), suggesting that PKC may not play significant roles in
shear stress–induced LOX-1 expression.
Fluid shear stress appears to stimulate transcription of the
LOX-1 gene. Since cycloheximide did not inhibit shear
stress–induced expression of LOX-1 mRNA (Figure 4), de
novo synthesis of proteins, such as transcription factors, is not
required in this process. NF-kB can be rapidly activated,
without de novo protein synthesis, by phosphorylation of
inhibitor kB and the subsequent dissociation from the p50/
p65 complex, which are followed by nuclear translocation of
p50/p65. The NF-kB p50/p65 heterodimer has been shown to
bind to the shear stress responsive element (SSRE) and
thereby activates the SSRE-dependent gene expression, such
as PDGF-B chain, in response to shear stress.33,42 In addition,
a previous report has also indicated that AP-1, as well as
NF-kB, can be activated by shear stress.31,33 Activation of
AP-1 has been shown to be responsible for shear stress–
induced transcription of the monocyte chemotactic protein-1
gene.32 Involvement of AP-1 and TPA responsive element are
also implicated in transcriptional downregulation of the
vascular cell adhesion molecule-1 gene.17,43 In transcriptional
regulation of PDGF-A chain by shear stress, interactions
between transcription factors Sp-1 and Egr-1 have also been
demonstrated.34,35 In the 59 flanking region of the LOX-1
gene, both consensus NF-kB–like sequence and SSRE have
been identified (data not shown). Further studies are necessary to elucidate the transcriptional regulatory mechanisms
involved in shear stress–induced LOX-1 gene expression.
In summary, the present study provides evidence, for the
first time, that physiological levels of laminar fluid flow shear
stress transcriptionally induce LOX-1 expression in BAECs
by a mechanism dependent on intracellular Ca21 mobilization. Endothelial expression of LOX-1, a novel receptor for
Ox-LDL, may also be dynamically modulated, in vivo, in
response to dynamic changes in blood flow. Although pathophysiological consequences of Ox-LDL uptake by vascular
endothelium through LOX-1 remain to be fully clarified,
modulated expression of this Ox-LDL receptor by fluid
mechanical stimuli may play an important role in the localized formation of atherosclerotic lesions in vivo.
Murase et al
Acknowledgments
This study was supported by Grants-in-Aid for Scientific Research
(Nos. 08407026, 08670788, and 09044293), for Scientific Research on
Priority Areas (09281103 and 09281104), and for Creative Basic
Research (09NP0601) from the Japanese Ministry of Education, Science, Sports, and Culture and by Research Grants for Cardiovascular
Diseases (A8-1) from the Ministry of Health and Welfare of Japan.
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Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Fluid Shear Stress Transcriptionally Induces Lectin-like Oxidized LDL Receptor-1 in
Vascular Endothelial Cells
Takatoshi Murase, Noriaki Kume, Risa Korenaga, Joji Ando, Tatsuya Sawamura, Tomoh
Masaki and Toru Kita
Circ Res. 1998;83:328-333
doi: 10.1161/01.RES.83.3.328
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