Circulation Journal  Vol.74,  April  2010
Circulation Journal
Official Journal of the Japanese Circulation Society
http://www.j-circ.or.jp
he lectin-like oxidized low-density lipoprotein (oxLDL)
receptor-1 (LOX-1) was originally identified as an
endothelial receptor for oxLDL.1 LOX-1 expres-
sion in vascular cells is relatively low in the normal state,
but can be induced by various stimuli such as oxLDL,2 tumor
necrosis factor-α (TNF-α),3 transforming growth factor-β1
(TGF-β1),4 interleukin-1β (IL-1β),5 angiotensin II,6,7 and endo-
thelin-1 (ET-1)8 in vitro. LOX-1 upregulation is involved in
oxLDL-induced apoptosis through the intracellular produc-
tion of reactive oxygen species.9,10 Endothelial expression of
LOX-1 in vivo is increased in hypertension (HT),11 diabetes
mellitus (DM),12 hyperlipidemia,13 hypercholesterolemia,14
and atherosclerosis.15 OxLDL-induced LOX-1 regulates the
expression of monocyte chemoattractant protein-1 (MCP-1),
a cytokine that mediates macrophage infiltration,16 and is con-
sidered to be involved in the pathogenesis of atherosclerosis
at an early stage.17 The membrane proximal extracellular
domain of LOX-1 can be proteolytically cleaved and released
as soluble forms.18 Levels of soluble LOX-1 (sLOX-1) in sera
are increased in acute coronary syndrome,19 type 2 DM,20
and obesity.21
LOX-1 expression in cultured cardiomyocytes is also very
low in the basal state, and can be induced by norepinephrine
and ET-1, neurohormonal factors that are activated in heart
failure (HF).22 The cardiac LOX-1 pathway is activated by
oxidative stress in vitro and by ischemia – reperfusion injury
in vivo.23 Although the activation of LOX-1 induces apop-
tosis in cardiomyocytes, the administration of anti-LOX-1
antibody is able to suppress their apoptosis in vitro22 and
reduces the extent of myocardial infarction (MI) in vivo.23
Left ventricular (LV) expression of LOX-1 is also increased
in salt-sensitive Dahl (DS) rats with hypertensive HF com-
pared with control normotensive salt-resistant Dahl (DR)
rats.24 The administration of eplerenone, an aldosterone
blocker, reduces LOX-1 activation and recovers the cardiac
function of DS rats.24 In the present study, we examined the
Received July 8, 2009; revised manuscript received December 22, 2009; accepted December 24, 2009; released online February 27,
2010 Time for primary review: 42 days
*Division of Translational Research, **Clinical Research Institute, Kyoto Medical Center, National Hospital Organization, †Department
of Cardiovascular Medicine, ††Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto and
‡Department of Vascular Physiology, National Cardiovascular Center Research Institute, Suita, Japan
‡‡The first two authors contributed equally to the work presented here.
Mailing address: Koji Hasegawa, MD, Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, National
Hospital Organization, 1-1 Mukaihata-cho, Fukakusa, Fushimi-ku, Kyoto 612-8555, Japan. E-mail: koj@kuhp.kyoto-u.ac.jp
ISSN-1346-9843 doi: 10.1253/circj.CJ-09-0488
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
Left Ventricular Expression of Lectin-Like Oxidized
Low-Density Lipoprotein Receptor-1
in Failing Rat Hearts
Tomohide Takaya, MA*,†,‡‡; Hiromichi Wada, MD*,‡‡; Tatsuya Morimoto, MD*;
Yoichi Sunagawa, MA*,††; Teruhisa Kawamura, MD*; Rieko Takanabe-Mori, MA*;
Akira Shimatsu, MD**; Yoshiko Fujita, PhD‡; Yuko Sato, PhD‡; Masatoshi Fujita, MD††;
Takeshi Kimura, MD†; Tatsuya Sawamura, MD‡; Koji Hasegawa, MD*
Background:  Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a multiple ligand receptor induced 
by oxidative stress. However, its role in chronic heart failure remains unknown.
Methods and Results:  The left ventricular (LV) expression of LOX-1 was examined in a salt-sensitive Dahl rat 
model of hypertension. Compared with controls, LOX-1 mRNA levels increased by 4.7-fold in the LV with hyper-
trophy, and by 32-fold in the LV with decreased systolic function. LV LOX-1 mRNA levels strongly correlated with 
the decrease in LV ejection fraction (EF) (r=−0.772), and with increases in the LV mRNA levels of B-type natri-
uretic peptide (r=0.814), monocyte chemoattractant protein-1 (r=0.943), transforming growth factor-β1 (r=0.936), 
and a macrophage marker, F4/80 (r=0.560). Serum levels of soluble LOX-1 were significantly elevated in patients 
with LV systolic dysfunction and hypertrophy, and significantly correlated with the decrease in EF (r=−0.495).
Conclusions:  Marked  increase  in  the  LV  expression  of  LOX-1  in  failing  hearts  may  contribute  to  increased 
serum  levels, and might be  involved  in chronic  inflammation during  the development of heart  failure.    (Circ J
2010; 74: 723 – 729)
Key Words:  Heart failure; Hypertension; Inflammation; LOX-1; Receptors
T
ORIGINAL  ARTICLE
Heart Failure

724
Circulation Journal  Vol.74,  April  2010
TAKAYA T et al.
correlation between LV expression of LOX-1 and progres-
sion of HF using Dahl rats. Furthermore, we found that serum
sLOX-1 levels are increased in patients with chronic HF and
LV hypertrophy (LVH).
Methods
Dahl Rats
Male Dahl rats were fed a low-salt diet (0.3% NaCl) until the
age of 6 weeks, after which, to induce HT, they were fed a
high-salt diet (8% NaCl). All animal experiments conformed
with the Guide for the Care and Use of Laboratory Animals
by the Institute of Laboratory Animals, Graduate School of
Medicine, Kyoto University, and the protocol was approved
by the Ethics Committee of the Graduate School of Medicine,
Kyoto University.
Physiological Analysis
Blood pressure (BP) was measured in the Dahl rats by the
tail-cuff method. Cardiac functions were noninvasively evalu-
ated by echocardiography, as previously described.25 In brief,
images were recorded using a 10- to 12-MHz phased-array
transducer (model 21380A with HP SONOS 5500 imaging
system; Agilent Technologies). LV end-diastolic and end-
systolic dimensions (LVEDD and LVESD) were measured
with M-mode tracings from the short-axis view of the LV at
the papillary muscle level. All measurements were per-
formed in a blinded fashion according to the guidelines of
the American Society for Echocardiology and averaged over
3 consecutive cardiac cycles. After physiological studies, sur-
viving rats were euthanased, and their hearts were removed.
Measurement of Plasma B-Type Natriuretic Peptide (BNP)
Blood samples were obtained from surviving rats for mea-
surement of plasma BNP concentrations using a radioim-
munoassay kit (Peninsula Lab).
Real-Time Reverse Transcriptase Polymerase Chain  
Reaction (RT-PCR)
Total RNAs from the LVs were isolated, reverse transcribed,
and subjected to quantitative real-time RT-PCR as previously
described.26 Primer sequences of LOX-1,27 BNP,28 MCP-1,29
TGF-β1,30 IL-1β,31 F4/80,32 and GAPDH26 have been de-
scribed previously.
Western Blotting
Whole cell lysates from rat LVs were prepared and subjected
to Western blotting as described previously,33 using mouse
monoclonal anti-LOX-11 and mouse monoclonal anti-β-actin
(Sigma) antibodies. Protein amounts were semi-automatical-
ly quantified by using Image J software (National Institutes
of Health).
Histological Analysis
The excised hearts were cut into 2 transverse slices at the
mid-level of the papillary muscles. The specimens were fixed
in 10% formalin, embedded in paraffin, sliced into 4-μm-thick
sections, and stained using mouse monoclonal anti-LOX-1
antibody.1
Human Subjects
A cross-sectional study was carried out during a specified
period between July and September 2007. Patients with
chronic congestive HF and LVH (CHF-LVH) and apparently
healthy subjects with normal cardiac function without LVH
(controls) were recruited in the Outpatient Department of
Cardiovascular Disease of Kyoto Medical Center. CHF was
defined according to the ACC/AHA Guideline.34 LVH was
defined as LV mass index (LVMI) >116 g/m2 in men and
>104 g/m2 in women on echocardiographic examination.
Chronic HF was defined as the patient being in a stable New
York Heart Association functional class for at least 3 months.
Most of the controls attended for further examination of
risk factors after periodical health checkup. The echocardio-
graphic criteria for CHF-LVH were defined as the presence
of LVH, ejection fraction (EF) <60%, and LVEDD >50 mm,
and those for controls were LVMI <100 g/m2, EF >60%, and
LVEDD <50 mm. Exclusion criteria were: (1) infection or
illness with pyrexia; (2) recent (<3 month) acute coronary
syndrome, MI, or stroke; (3) chronic, systemic illness, includ-
ing renal failure, hepatic impairment, cancer, and inflamma-
tory connective tissue disease; inflammatory bowel disease.
BP was measured twice with an automatic electronic sphyg-
momanometer (BP-103i II; Nippon Colin, Komaki, Japan).
The study protocol was approved by the Institutional
Ethics Committee of Kyoto Medical Center.
Table 1. Morphometric and Hemodynamic Parameters of Dahl Rats
6 weeks 11 weeks 18 weeks
DR DS DR DS DR DS
N 5 5 5 5 4 4
BW (g) 207±5　 178±4*　 374±13　 327±8*,†　 479±9　   333±11*,†
LVW/BW 2.38±0.02 2.40±0.02 2.19±0.12   2.85±0.12*,† 1.84±0.06   3.16±0.16*,†
SBP (mmHg) 107±2　 113±3　 130±6　 191±8*,†　 126±3　   213±10*,†
DBP (mmHg) 64±8　 69±6　 105±6　 141±5*,†　 96±2　 149±7*,†　
Heart rate (beats/min) 449±11　 405±25　 417±20　 404±13　 376±13　 354±33　
LVESD (mm) 3.21±0.13 2.80±0.31 4.15±0.25   3.15±0.26† 5.26±0.18   5.47±0.81†,‡
LVEDD (mm) 7.49±0.22 7.01±0.42 8.63±0.28   7.61±0.21* 9.37±0.15 8.27±0.74
LVPWT (mm) 0.93±0.07 0.98±0.10 1.31±0.12   1.73±0.07*,† 1.25±0.17   2.03±0.18*,†
EF (%) 91.9±1.2　 93.6±1.2　 88.2±2.3　 92.8±1.1　 82.2±1.3　   71.2±5.6†,‡
Plasma BNP (pg/ml) 113±13　 98±1　 120±18　 137±18　 108±8　 303±97†　
Data are means ± SE. *P<0.05 vs corresponding DR; †P<0.05 vs DS at 6 weeks; ‡P<0.05 vs DS at 11 weeks.
DR, salt-resistant Dahl; DS, salt-sensitive Dahl; BW, body weight; LVW, left ventricular (LV) weight; SBP, systolic 
blood pressure; DBP, diastolic blood pressure; LVESD, LV end-systolic dimension; LVEDD, LV end-diastolic dimen-
sion; LVPWT, LV posterior wall thickness; EF, ejection fraction; BNP, B-type natriuretic peptide.

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Circulation Journal  Vol.74,  April  2010
LV Expression of LOX-1 in HF
Measurement of sLOX-1
Patients’ blood samples were taken from the antecubital vein
in the morning after a 12-h fast. Blood was immediately cen-
trifuged and the serum obtained was divided into aliquots.
Serum sLOX-1 concentrations were measured by ELISA.
The analyses were performed by an investigator who was
unaware of the source of each sample.
Statistical Analysis
Results are presented as means ± SE. Statistical comparisons
were performed using ANOVA with Scheffe’s test. Linear
regression analysis with Pearson’s coefficients was performed
to investigate correlations. The Mann-Whitney U test was
used for comparisons of human sLOX-1. P<0.05 was taken
to indicate significance.
Results
Development of HF in Dahl Rats
Cardiac function of the Dahl rats was assessed before and
after (at 11 and 18 weeks) they were fed a high-salt diet from
the age of 6 weeks. As shown in Table 1, BP was significant-
ly higher than in the DS compared with the DR rats at 11 and
18 weeks. Accordingly, DS rats exhibited LVH: increased
LV weight-to-body weight ratio (LVW/BW) and LV poste-
rior wall thickness (LVPWT) compared with DR rats at 11
and 18 weeks. The LVEF of DS rats was preserved at 11
weeks but significantly reduced at 18 weeks. These data dem-
onstrate that DS rats showed progressive LVH at 11 weeks,
followed by systolic dysfunction at 18 weeks. The LVW/
BW ratio was significantly higher in the DS (5.14±0.30) than
in the DR (3.71±0.04) rats at 18 weeks. The increased lung
weights and plasma BNP levels in the DS compared with the
DR rats suggest that the LV end-diastolic pressure increased
at 18 weeks. LV dilatation would subsequently occur after
18 weeks in the DS rats. However, LV dilatation was not
observed in this series of experiments, because DS rats rap-
idly die after 18 weeks and the time period of LV dilatation is
very short.
LV Expression of LOX-1 in Dahl Rats
Real-time RT-PCR analysis indicated that LV mRNA levels
of LOX-1 in the DS rats progressively increased at 11 and 18
weeks, while those in the DR rats did not change (Figure 1A).
LOX-1 expression revealed 4.7- and 32-fold increases in the
DS compared with the DR rats at 11 and 18 weeks, respec-
tively. Compatible with the mRNA levels, the amount of
LOX-1 protein in the LV was greater in the DS rats than in
the DR rats at 18 weeks (Figure 1B). DS rats showed a 5.8±
3.3-fold increase in the levels of LOX-1 protein compared
with the DR rats at 18 weeks. Sections of LV from these
rats at 18 weeks were stained using anti-LOX-1 antibody
(Figure 1C). LOX-1 immunoreactivity was observed in
vessel walls and very faintly in the cardiomyocytes of DR
rats. However in the DS rats, LOX-1 was strongly and clearly
detected in cardiomyocytes as well as vessel walls. These
Figure 1.    (A) Results of real-time RT-PCR. The amount of  transcript  for LOX-1 was normalized by that of GAPDH. The data 
shown are means ± SE. The mean value of DR rats at 6 weeks was set at 1.0. The number of animals in each group is shown in 
Table 1. *P<0.05, **P<0.01, ***P<0.005. (B) Whole cell lysates from the LV of Dahl rats at 18 weeks were subjected to Western 
blotting with anti-LOX-1 and anti-β-actin antibodies. (C) Representative photographs of LOX-1-stained sections of LV myocar-
dium from Dahl rats at 18 weeks. Scale bar=20 μm. DR, salt-resistant Dahl rat; LOX-1, lectin-like oxidized low-density lipoprotein 
receptor-1; LV, left ventricle; RT-PCR, reverse transcriptase polymerase chain reaction; w, weeks.

726
Circulation Journal  Vol.74,  April  2010
TAKAYA T et al.
results clearly indicate that the expression of LOX-1 in LV
cardiomyocytes was upregulated during the development of
LVH and HF in DS rats.
LV Expression of Cytokines Involved in HF
Levels of the mRNA of BNP, MCP-1, TGF-β1, IL-1β, and
F4/80 in the LV were also quantified by real-time RT-PCR
(Figure 2). Those of BNP, which reflect the extent of LV
wall stress, were increased in the DS rats during the devel-
opment of HF and were significantly higher than those of the
DR rats at 18 weeks (Figure 2A). Those of MCP-1 in the DS
rats showed 2.1- and 10.2-fold increases at 11 and 18 weeks,
respectively, compared with the DR rats (Figure 2B). Those
of TGF-β1 (Figure 2C) and IL-1β (Figure 2D) showed 3.1-
and 2.9-fold increases, respectively in the DS compared with
the DR rats, at 18 weeks. Compatible with the increased
expression of these cytokines in the DS rats, the LV mRNA
level of F4/80, a marker of macrophages, showed 1.9- and
3.7-fold increases at 11 and 18 weeks, respectively, in the
DS compared with the DR rats (Figure 2E).
Correlation Between LOX-1 Expression and Parameters of HF
As shown in Table 2, LV mRNA levels of LOX-1 positively
correlated with the levels of HT (systolic and diastolic BP)
and LVH (LVW/BW and LVPWT). LOX-1 expression was
also associated with deterioration of systolic function (in-
crease in LVESD and decrease in EF, Figure 3A). In addi-
tion, LOX-1 strongly indicated positive correlations with the
plasma and mRNA levels of BNP (Figure 3B). Thus, LOX-1
expression was closely associated with the extent of HF in
Dahl rats. Importantly, the LV mRNA levels of LOX-1 were
most closely correlated with those of MCP-1 (Figure 3C).
The levels also strongly correlated with those of TGF-β1
(Figure 3D) and IL-1β (Figure 3E). In addition to these
cytokines, the LV mRNA levels of LOX-1 significantly cor-
related with those of F4/80 (Figure 3F).
Figure 2.    Results of real-time reverse transcriptase polymerase chain reaction. The amount of each of the transcripts for BNP 
(A), MCP-1 (B), TGF-β1 (C), IL-1β (D), and F4/80 (E) was normalized by that of GAPDH. Data are means ± SE. The mean values 
of  DR  rats  at  6  weeks  were  set  at  1.0.  The  number  of  animals  in  each  group  is  described  in  Table 1.  *P<0.05,  **P<0.01, 
#P<0.005,  ##P<0.001. BNP, B-type natriuretic peptide; DR,  salt-resistant Dahl  rat; DS,  salt-sensitive Dahl  rat;  IL,  interleukin; 
MCP-1, monocyte chemoattractant protein-1; TGF, transforming growth factor; w, weeks.
Table 2. Correlation Between LOX-1 mRNA and Parameters
of Heart Failure
vs LOX-1/GAPDH
R P value
LVW/BW 0.620 0.0004
SBP 0.748 <0.0001　
DBP 0.604 0.0007
Heart rate –0.426　 0.0268
LVESD 0.555 0.0022
LVEDD 0.172 0.3808
LVPWT 0.638 0.0002
EF –0.772　 <0.0001　
Plasma BNP 0.744 <0.0001　
BNP/GAPDH 0.814 <0.0001　
MCP-1/GAPDH 0.943 <0.0001　
TGF-β1/GAPDH 0.936 <0.0001　
IL-1β/GAPDH 0.760 <0.0001　
F4/80/GAPDH 0.560 0.0019
Correlations between LV mRNA levels of LOX-1 and parameters 
of heart failure for all 28 rats shown in Table 1.
GAPDH,  glyceraldehyde-3-phosphate  dehydrogenase;  MCP, 
monocyte  chemoattractant  protein;  TGF,  transforming  growth 
factor; IL, interleukin. Other abbreviations see in Table 1.

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Circulation Journal  Vol.74,  April  2010
LV Expression of LOX-1 in HF
Figure 3.    Correlations between  the LV mRNA  levels of LOX-1 and  the parameters of heart  failure. Abbreviations see  in 
Tables 1 and 2.
Table 3. Clinical and Echocardiographic Measurements of Human Subjects
Controls CHF-LVH patients P value
n (M/F)  11 (7/4)   7 (4/3)
Age (years) 64.8±4.4　 67.7±3.8　 NS
BMI (kg/m2) 24.0±1.3　 22.9±1.5　 NS
SBP (mmHg) 125.8±5.3　　 113.4±3.7　　 NS
DBP (mmHg) 74.5±4.2　 61.9±3.4　 0.077
Heart rate (beats/min) 71.8±4.2　 76.8±5.0　 NS
LVEDD (mm) 42.1±1.0　 64.1±4.7　 <0.001　
EF (%) 71.5±1.9　 37.5±2.9　 <0.001　
LV mass (g) 115.1±6.5　　 247.8±33.9　 <0.001　
LVMI (g/m2) 71.7±4.9　 157.3±26.2　 <0.001　
Diabetes mellitus, n (%) 0 (0)   4 (57)
History of hypertension, n (%) 0 (0)   4 (57)
Etiology of CHF, n (%)
    Ischemic 0 (0)   4 (57)
    Non-ischemic 0 (0)   3 (43)
    Idiopathic dilated cardiomyopathy 0 (0)   3 (43)
NYHA functional class, n (%)
    I   11 (100) 0 (0)
    II 0 (0)   6 (86)
    III 0 (0)   1 (14)
    IV 0 (0) 0 (0)
Data are means ± SE.
Controls,  no  organic  cardiac  diseases;  CHF-LVH,  chronic  heart  failure  with  LV  hypertrophy;  NS,  not  significant; 
NYHA, New York Heart Association. Other abbreviations see in Table 1.

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TAKAYA T et al.
Serum Levels of sLOX-1 in Chronic HF Patients
The clinical and echocardiographic measurements in the
patients with CHF-LVH and the apparently healthy subjects
with normal cardiac function (control) are shown in Table 3.
LVEDD, LV mass, and LVMI were significantly larger and
EF significantly lower in the CHF-LVH patients than in the
control group. However, there were no significant differences
in age, body mass index, BP, and heart rate between the 2
groups. Interestingly, serum levels of sLOX-1 were signifi-
cantly increased in the CHF-LVH group compared with the
controls (Figure 4). In simple regression analysis, there was a
weak, but non-significant correlation between serum sLOX-1
levels and LVMI (r=0.437, P=0.07). However, there was a
significant negative correlation between serum sLOX-1 levels
and EF (r=−0.495, P=0.037). Since previous reports have
shown that sLOX-1 levels are increased in patients with DM
and those with HT, we compared the sLOX-1 levels in CHF-
LVH patients with and without DM or HT. There was no
significant difference in the sLOX-1 levels of CHF-LVH
patients with and without DM or HT (DM 892±316 pg/ml
vs non-DM 1,023±311 pg/ml, P=0.8; HT 845±275 pg/ml vs
non-HT 1,086±366 pg/ml, P=0.6). To evaluate whether the
etiology of chronic HF affects sLOX-1 levels, we compared
sLOX-1 levels in patients with CHF-LVH caused by ischemic
heart disease (IHD) with those in patients with CHF-LVH
caused by dilated cardiomyopathy (DCM). There was no
significant difference (P=0.5): IHD, 1,083±348 pg/ml; DCM,
769±178 pg/ml.
Discussion
In the present study, we showed that levels of mRNA and
LOX-1 protein were markedly upregulated in the LV of DS
rats with HF, which was compatible the results of a previous
report.24 We have found that LV mRNA levels of LOX-1
closely correlated with decreased EF and increases in the
plasma and mRNA levels of BNP. These findings suggest
that LV expression of LOX-1 serves as a novel biomarker of
HF in hypertensive heart disease. We have also shown that
the serum levels of sLOX-1 were significantly increased in
chronic HF patients with LVH and that they correlated with
the decrease in EF. Thus, a marked increase in the LV
expression of LOX-1 in the failing heart may significantly
contribute to increased serum levels of sLOX-1. However,
the origin of increased serum sLOX-1 levels during hyper-
tensive heart disease should be examined in further studies,
because HT enhances LOX-1 expression not only by the
heart, but also by the vascular endothelium.11
LV mRNA levels of LOX-1 showed a very strong positive
correlation with those of MCP-1, an important chemotactic
factor for macrophages. LOX-1 expression also closely cor-
related with those of TGF-β1 and IL-1β, proinflammatory
cytokines produced by macrophages. Furthermore, LV ex-
pression of LOX-1 positively correlated with that of F4/80,
a maker of macrophages, suggesting that increased LOX-1
expression is involved in macrophage infiltration and inflam-
mation. In the heart, MCP-1 expression and the number of
interstitial macrophages in the LV are significantly increased
in models of hypertensive heart disease with HF31 and of
post-MI HF.35 The number of macrophages in the LV myo-
cardium shows nearly a 4-fold increase in DS compared with
DR rats at 11 and 18 weeks.31 Our results for the LV mRNA
levels of F4/80, a marker of macrophages, are compatible
with those of the previous report.
MCP-1 is considered to be downstream of LOX-1 because
the antisense to LOX-1 inhibits MCP-1 expression in endo-
thelial cells.17 Inhibition of MCP-1 in a mouse MI model
reduced macrophage infiltration and the levels of cytokines
such as TGF-β1 in the heart.35 It has also been reported that
anti-LOX-1 antibody reduces IL-1β expression in vascular
cells.36 Our results indicated that LOX-1 upregulation in the
LV of DS rats compared with DR rats was most prominent
at the stage of systolic HF. Furthermore, LV expression of
LOX-1 showed a close relationship with that of inflam-
matory cytokines, as well as MCP-1 and F4/80, which are
markers of increased macrophage infiltration. These findings
suggest that LOX-1-induced MCP-1 enhances macrophage
infiltration, and that the migrating macrophages then produce
proinflammatory cytokines in the heart. TGF-β1 and IL-1β
are well-known inducers of LOX-1,4,5 so it is possible that
increased LOX-1, macrophage infiltration, and the release of
inflammatory cytokines may form a feed-back loop that
progresses to fibrosis and apoptosis during the progression
of HF. At present, it is unknown whether activation of LV
LOX-1 is a cause or result of HF. However, our results,
together with those of previous reports, suggest that upregu-
lation of LOX-1 in HF is a very important key event, leading
to inflammation of the heart. The development of a specific
antagonist is awaited to clarify the precise role of LOX-1,
and to investigate the therapeutic potential of the antagonist
for chronic HF.
Acknowledgments
We thank Mika Kiriyama, Noboru Chiba, Shuichi Ura, Akira Yamada,
and Yuko Iida for their technical assistance and Akemi Wada for secre-
tarial assistance. This work was supported by grants in-aid for scientific
research awarded to K. Hasegawa from Ministry of Education, Culture,
Sports, Science and Technology of Japan and from Research on Publicly
Essential Drugs and Medical Devices, The Japan Health Sciences Foun-
dation, and awarded to H. Wada from Suzuken Memorial Foundation,
Japan Research Foundation for Clinical Pharmacology, and the Smoking
Research Foundation.
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Figure 4.    Serum levels of soluble LOX-1 (sLOX-1) in chronic 
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trol, n=11). LOX-1, lectin-like oxidized low-density lipoprotein 
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