Extract
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Introduction
Leptin, a product of the OB-gene, is originally
associated with energy expenditure and weight loss. The
expression of leptin and its receptors has been detected in several
non-adipose tissues, including the
myocardium[1]. An increase in leptin has been implicated in the development of
cardiovascular diseases and conditions, including coronary
heart diseases[2],
stenting[3], and
hypertension[4]. Hyper-leptinemia is involved in the increased activity of the
sympathetic nerve system and is closely linked with the
occurrence of cardiovascular events such as myocardial
infarction[5] and stroke, suggesting that leptin may participate in
proatherogenic mechanisms at vascular intima. Leptin
receptors (OB-Rb or OB-RL) regulate the central actions of
leptin and has also been detected in various other
tissues including cardiomyocytes[1].
There is considerable interstitial fibrosis in chronic heart
failure (CHF), which stiffens ventricles and impedes both
contraction and relaxation. The increased expression of a
number of extracellular matrix proteins, including several
forms of collagen and fibronectin, matrix metalloproteinases
(MMP), and the downregulation of their inhibitors [tissue
inhibitor of metalloproteinases (TIMP)] are responsible for
the formation of the extracellular matrix (ECM), which is
intimately involved in the remodeling of the cardiac
matrix[6]. Changes in MMP and TIMP expression or activity are
related to an excessive reactive oxygen species (ROS) during
the progression from compensated to decompensated heart
failure. The state of oxidative stress associates the
myocardium with the induction of cardiac remodeling, cardiomyocyte
hypertrophy, the activation of MMP, and inflammatory
cell infiltration[7]. Recent studies provide evidence that
patients with CHF exhibit an average increase
in serum levels of leptin as compared to healthy
controls[5]. Leptin enhances the MMP-2 and MMP-9 expression
in vitro, and increases the generation of intracellular ROS in
cardiomyocytes[8_10]. Moreover, pro-inflammatory cytokines correlate well with
circulating levels of leptin, and hyperleptinemia in several
chronic diseases has been linked to the activation of an
inflammatory marker of tumor necrosis factor
(TNF-α)[11,12]. An increase in TNF-α in the plasma in clinical findings is
directly correlated to the progression of CHF.
Interestingly, with anti-inflammatory and
immunosuppressive properties, dexamethasone (Dex) inhibits the
leptin_activated transcription (STAT) 3 signaling pathway in a
cultured cell line as well as in the rat
hypothalamus[13]. Dex also has protective effects against
TNF-α-mediated cell death[14]; however, Dex significantly upregulates leptin levels and
leptin receptors, then causes an increase in OB gene
expression and leptin secretion in isolated adipose tissue from
rodents and humans[15,16]. In general, leptin is a risk factor for
cardiovascular diseases, and marked leptin increase in the
plasma and myocardium has been found in patients of CHF.
The behavior of leptin in relation to the cardiovascular
system varied[17,18]; leptin might do insult to the myocardium,
but it is also likely to be beneficial to the heart. It would be
interesting to see whether the upregulation of leptin is an
important marker only in the development of
CHF[5]. Dex might inhibit the leptin pathway, and also up-regulate
expression of leptin and its receptors. Thus, we hypothesized
that an up-regulation of leptin levels, protein expression and
its receptor OB-RL contributed to CHF, it is true, however,
with Dex intervention, an up-regulation of leptin and its
receptor OB-Rb might not be down-regulated despite a
significant relief of CHF is achieved. It is interesting to investigate
whether an elevated leptin in serum is critical to induce
cardiac insufficiencyby its direct action on its receptors OB-Rb
in myocardium, or it is a marker only and exerts a combined
effect with other cytokines responsible to compromised
cardiac function. Thus it is interesting to investigate if we could
separate leptin from other inflammatory factors for its
adverse relationship to CHF under certain condition. Based on
the effectiveness of Dex on cardiac ischemia and heart failure,
we applied Dex to observe whether hyperleptinemia and an
up-regulation of leptin receptors OB-Rb could not be
substantially related to CHF and Dex-induced relief of CHF was
associated with suppression of TNF-α, MMP-2 and MMP-9
and ROS, when hyperleptinemia, but not with up-regulation
of leptin and its receptors in myocardium.
Materials and methods
Animals Male Sprague-Dawley rats (200_220 g, aged 10
weeks) were used for the experiment. They were housed in a
controlled environment and allowed free access to tap water
and food.
Experimental heart failure CHF was developed by
coronary artery ligation in rats for 5 weeks. Briefly, the left
coronary artery was ligated between the left atrial appendage
and the right ventricular outflow tract with a 6.0 silk suture.
The chest was then closed in layers and air was evacuated
from the chest cavity by slight lateral pressure of the thorax.
Using this method, the survival rate was 60%_70% at 24 h
after the operation. Sham operations were performed to open
the pericardium only, but no ligation was made around the
coronary artery. The rats were weighed every week and
their food intake was measured to adjust the doses of Dex.
Experiment protocol The rats were divided into 3 groups:
(i) the sham operation (sham) group; (ii) chronic heart failure
(CHF) group; and (iii) the CHF rats treated with (Dex), which
was added in the drinking water (1 µg/mL, Xianju
Pharmaceutical Co Ltd, China). The actual dose of Dex was
approximately 50
mg×kg-1×d-1. Water containing Dex was prepared
freshly everyday. In each group, the number of animals was
10, except in the expression experiment where
n=4.
Hemodynamic changes In brief, the rats were
anesthetized with urethane (1.5 g/kg, ip) 6 weeks after the surgical
operation, and the right carotid artery was cannulated with a
micromanometer-tipped catheter (PE 50, ID 0.58 mm, OD
0.965 mm, Becton Dickinson and Company, San Jose, CA,
USA) which was connected to a pressure transducer
(MPA-V, the Second Military Medical University, Shanghai, China)
and advanced into the left ventricle (LV). The LV
(+dp/dtmax and
_dp/dtmin), left systolic pressure (LVSP), and left
ventricular end diastolic pressure (LVEDP) were recorded. The
heart rate was monitored by lead electrocardiogram.
Cardiac morphological assay After the experiments, the
LV myocardium was fixed in 10% formalin. Three cross
sections in the noninfarcted myocardium, from the apex to the
base, were obtained and compared among the 3 groups.
Assessment of myocardial hypertrophy and interstitial
fibrosis were conducted in slices with HE stain, and
Masson's trichrome stain, separately. The diameter of the
cardiomyocytes was evaluated by direct measurements at ×400
magnification in cross sections that included a nuclear profile.
A total of 40 cells per section were evaluated. For the
evaluation of fibrosis in the myocardium, imaging scanning
technique of the Masson's stained slices was performed in 3
sections per animal and 20 fields per section, and
computerized with a digital image analyzer (Image-pro Plus, Media
Cybernetics Inc, Silver Spring, MD, USA). The volume of
collagen fraction was calculated as the sum of all connective
tissue areas divided by the total area of the
image[19].
Biochemical parameters of CHF The measurement of
glutamic oxaloacetate transaminase (GOT), glutamic
pyruvate transaminase (GPT), malondialdehyde (MDA),
superoxide dismutase (SOD), glutathione peroxidase (GSH-Px),
catalase (CAT), xanthine oxidase (XOD), lactate
dehydrogenase (LDH), creatine phosphokinase (CPK) in the serum, and
hydroxyproline (HYP) in the left ventricles were conducted
in all the rats of the 3 groups.
Radioimmunoassays of plasma leptin Plasma leptin
concentrations were measured in duplicate using a specific rat
leptin radioimmunoassay kit (Linco Research, St Charles, MO,
USA). The interassay coefficient of the variation was less
than 6%, and the detection limit was 0.5 ng/mL.
RT-PCR Total RNA was extracted using Trizol reagent
(Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions. Five micrograms of RNA was
used to synthesize the first strand of cDNA using
SUPERSCRIPT II RNase H-Reverse Transcriptase (Invitrogen,
Carlsbad, CA, USA) according to the manufacturer's
protocol, and was used as a template in the following PCR
reactions.
To elucidate the mRNA expression of MMP-2,
MMP-9, TIMP-1, TIMP-2 and OB-Rb (leptin receptors) , RT-PCR
was carried out using sense primers and antisense primers.
Sense: 5'-CCCAGAAAAGATTGACGC-3' and antisense: 5'-CGACAGCATCCAGGTTAT-3' for MMP-2; sense:
5'-CGT-GGCCTAGTGACCTATG-3' and antisense:
5'-GGATAGCTC-GGTGGTGTCCT-3' for MMP-9; sense:
5'-GCTGCGGTTCT-GGGATT-3' and antisense:
5'-CCTCTGGCATCCTCTTGTT-3' for TIMP-1; sense: 5'-GAAGAAAGGAGGTTGCAGT-3' and
antisense: 5'-TCCAGGAAGGGATGTCAAAG-3' for TIMP-2; sense: 5'-GCTGAGAGCACCCAGGGAACC-3' and
anti-sense: 5'-GTTTCCTGGCGATGCACTGGC-3' for OB-Rb. The
products were resolved on 3% agarose gel followed by
ethi-dium bromide staining.
Zymography of MMP-2 and MMP-9 The proteins were
extracted from the cardiac tissue. Briefly, the LV were
homogenized in lysis buffer containing 1% SDS, 1 µmol/L
phenylmethylsulfonyl fluoride (PMSF), and 10 µg/mL
leupeptin in 50 mmol/L Tris buffer at pH 7.6. Insoluble matter
was removed by centrifugation at 10
000×g for 10 min. The total protein concentration for each sample was determined
using the Bradford method. Gelatin was incorporated into
10% SDS-PAGE to a final concentration of 1 mg/mL. After
electrophoresis, the proteins in the gel were denatured by
incubation for 30 min (2×15 min) in 2.5% Triton X-100. The
gels were subsequently incubated overnight at 37 °C in 50
mmol/L Tris-HCl, pH 7.4, containing 10 mmol/L of calcium
chloride. Bands of lytic activity were visualized as zones of
clearing after staining with Coomassie brilliant blue G-250.
To verify MMP activity, identical gels were incubated
overnight in the presence of 20 mmol/L of EDTA, an inhibitor of
MMP, and 2 mmol/L of PMSF, a serine protease inhibitor.
Western blotting For the quantitative analysis of the
leptin protein level in the myocardium, the LV tissue
(100_200 mg) was homogenized in 4 volumes of extraction buffer
and centrifuged at 10 000×g for 10 min. After determination
of the protein concentration, the supernatants were stored
at _20 °C until use. An aliquot was heated to 95 °C, and
size-fractionated on 10% SDS-PAGE. The extracted protein was
transferred to a nitrocellulose membrane and blocked with
nonfat milk (5% w/v), followed by incubation with first
antibody (1:100, BA1231, Boster Biological Technology Ltd,
Wuhan, China) for another 1 h. After 3 washes, the blot was
incubated with horseradish peroxidase conjugated goat
secondary antibody IgG (1:1000) for an additional 1 h. Antigen
was detected with a DAB kit. A linear relationship between
the density of blots and the protein load was observed when
20, 40, 60, 80, and 100 μg of membrane protein was used per
lane.
Statistic analysis GraphPad Prism, version 4.0 (GraphPad
Software Inc, San Diego, CA, USA), was used to analyze the
results. Data are presented as mean±SD. The paired
Student's t-test was used for the statistical comparison of
mean values between 2 experimental groups. One-way
ANOVA and Bonferroni test were used to compare mean
values between all experimental groups. A value of
P<0.05 was considered statistically significant.
Results
Improvement of hemodynamics and cardiac
remodeling Chronic coronary ligation markedly deteriorated cardiac
systolic LVSP (-18.4%) and LV
+dp/dtmax (-27.7%) and diastolic
function (LV_dp/dtmin (-27.6%), and elevated LVEDP
(+82.2%; P<0.05, P<0.01), respectively. Dex significantly improved
cardiac function (P<0.05, P<0.01), respectively. An increased
heart rate (+19.6%, P<0.05) was seen in the CHF group, and
it was also suppressed markedly by Dex treatment (Table 1).
Remodeling of the myocardium was assessed
morphologically and biochemically in CHF rats (Figure 1A; Table
2). The cardiac weight indice, a fraction of heart weight to body
weight (HW/BW) and left and right ventricle weight to body
weight (LVW/BW, RVW/BW, mg/g), increased by 27.2%
(P<0.01), 36.0% (P<0.01), and 33.3%
(P<0.01), respectively, compared with the sham group. Dex
could effectively
regress the increment in the cardiac weight indice
significantly (P<0.05), compared with the CHF group (Table 2).
HE staining showed that the diameter of cardiac muscle
fiber in the noninfarcted zone (free left ventricular wall) was
significantly elongated in the CHF group compared with the
sham group (P<0.05; Figure 1B). Masson staining showed
an increase in blue staining indicating fibrosis of the
myocardium in the rats with CHF.
The density of blue staining was markedly reduced after
Dex treatment (Figure 1A). Semiquantitative scanning
demonstrated that the fraction of collagen volume significantly
increased by approximately 6 times compared with the sham
group (P<0.01; Figure 1C). The level of myocardial
hydroxyproline increased by 47.0% (P<0.01) in the CHF group
compared with the sham group (Figure 1D). These abnormalities
reflected significant cardiac remodeling during chronic heart
failure and Dex treatment significantly reversed these
changes induced by CHF (P<0.01).
Activity of cardiac enzymes in serum The marked
elevations of GOT (+32.5%, P<0.01), GPT (+176.6%,
P<0.01), LDH (+34.6%, P<0.05), and CPK (+22.2%,
P<0.01) were observed in CHF group compared with the sham group. Dex treatment
significantly reduced the elevation of the activities of the
marker enzymes in serum (Table 3).
Oxidative stress and TNF-α mRNA
expression There was significant changes in the activities of the redox system,
SOD (-30.5%), MDA (+64.0%), GSH-Px (-19.6%), CAT
(-34.7%), and XOD (+26.3%) in the serum in the CHF group
compared to the sham group (P<0.01). Dex markedly reversed
these changes in SOD, MDA, GSH-Px, CAT, and XOD
induced by CHF (P<0.01, Table 4).
Compared with the sham group, TNF-α mRNA expression was up-regulated by 94.3%
(P<0.01) in the CHF group. Dex treatment significantly suppressed the increase in
TNF-α mRNA expression induced by CHF (P<0.01, Figure 2).
The mRNA expression and activities of MMP-2, MMP-9,
TIMP-1, and TIMP-2 The mRNA expression of MMP-2 and
MMP-9 was up-regulated by 112% (P<0.01) and 44.6%
(P<0.01), respectively in the CHF group compared with the
sham group. Dex significantly decreased upregulated mRNA
expression of MMP-2 and MMP-9 induced by CHF
(P<0.05 and P<0.01), respectively (Figure 3A, 3B). The mRNA
expression of TIMP-1 and TIMP-2 was significantly
down-regulated by 44.3% (P<0.05) and
44.1% (P<0.05), respectively in CHF group compared with the sham group. Dex markedly
increased the down-regulation of the mRNA expression of
TIMP-1 and TIMP-2 induced by CHF (P<0.01 and
P<0.05, Figure 3C, 3D).
The lytic activities of MMP-2 and MMP-9 were
significantly increased compared with the sham group (Figure 3E).
Dex dramatically decreased elevated metalloprotein-ase activities induced by CHF (Figure 3F).
Serum leptin level and leptin receptor
expression Hyperleptinemia was observed in the CHF group
(P<0.01). The serum leptin level of the CHF group was 2 times higher
compared with the sham group (Figure 4A). OB-Rb mRNA
expression in the myocardium significantly increased by 104%
in the CHF group compared with the sham group
(P<0.01, Figure 4B). The leptin protein expression in the myocardium
of the CHF group was also markedly up-regulated compared
with the sham group (P<0.01; Figure 4C). There were no
significant differences in the serum leptin level, mRNA
expression of OB-Rb in myocardium, and leptin protein
expression between the Dex-treated CHF group and the CHF
group (P>0.05).
Discussion
Leptin, a 16 kDa peptide, was produced primarily by
adipocytes. It is referred to as an anti-obesity hormone due
to its inhibitory effects on food intake and stimulating
effects on energy expenditure. The heart is a site of leptin
production and its action is mediated by a group of a soluble
form of leptin receptors[1]. One of the isoforms of the receptor,
known as the long form (OB-Rb), is considered to represent
the full signaling isoform of the leptin receptor (OB-Ra,
OB-Rb, OB-Rc, OB-Rd, OB-Re, and OB-Rf). In this study , we
observed that an upregulation of serum leptin levels, leptin
protein expression, and mRNA expression of leptin receptor
OB-Rb was associated with impaired cardiac function after
CHF, which was in agreement with hyperleptinemia
following myocardial infarction[5], and the upregulated leptin
receptor in the myocardium of failing
hearts[6].
The upregulation of TNF-α found in CHF group was
linked with an increase in serum leptin level. Both
TNF-α and leptin inhibited cardiac contractile function
independently and synergistically[17]. The production of
TNF-α in injured myocardium was promoted by leptin, so the 2
cytokines co-contributed to the morbidity of
CHF[18].
Change in the extracellular matrix in the myocardium,
primarily responsible for cardiac remodeling, is mediated by an
increase in activities of MMP, which can collectively
degrade all structural extracellular matrix proteins of the failing
hearts[20]. During the process of CHF, MMP are initially
activated to reduce wall stress and allow dilation against an
increased workload induced by increasing fibril collagen
degradation. In this study, the expression and activities of
MMP were upregulated significantly in the CHF group in
association with a reduction in mRNA expression of the
endogenous inhibitor TIMP-1 and TIMP-2 in the myocardium.
Cardiac structure changes are attributed to abnormal
expression of MMP-2, MMP-9, TIMP-1 and
TIMP-2. Interstitial fibrosis is commonly exhibited at the end stage of dilated,
ischemic, and valvular cardiomyopathy, but it can be
discriminated by variations in volume density of type III
collagen and laminin, and MMP in the
myocardium[21]. Cardiac function of the chronic infarcted heart could be deteriorated
by an activated MMP-2, MMP-9, and reduced TIMP-1 and
TIMP-2. In the myocardium, the ultrastructural collagen,
initially degraded by MMP, is replaced by poorly-structured
collagen; then cardiac remodeling takes place. Some MMPs
leak into the blood circulation after myocardial infarction, so
the serum MMP level can be used to predict the occurrence
of congestive heart failure in patients with myocardial
infarction during a 2-year follow up period. It is interesting to
find that elevated level of MMP-9, rather than the levels of
TNF-α, the C-reactive protein, or MMP-2, may be a
significant risk factor for the late onset of CHF in patients with
acute myocardial infarction[22]. The upregulation of MMP-2
in the myocardium is significant in CHF patients and
contributes to cardiac remodeling; however, on the other hand
the up-regulated MMP-2 had beneficial effects on CHF
patients. Cardiomyopathy induced by over-expression of
TNF-α in transgenic mice was associated with cardiac
remodeling and heart failure and up-regulation of MMP-2.
In MMP-2 knockout (MMP-2 [-/-]) mice, the zymographic
activity of MMP-2 is completely abolished; however,
cardiac function is worsened and the survival time is shortened
compared with the wild-type MMP-2 mice. Thus, the
upre-gulation of MMP-2 in the process of CHF could be a
protective factor in TNF-α-induced
cardiomyopathy[23]. We
observed that Dex attenuated myocardial remodeling and
inhibited the MMP activities which coincided with previous
findings[24].
Oxidative stress is found predominantly in CHF and
contributes to myocardial remodeling by activating MMP-2 and
MMP-9 and depressing TIMP-1 and TIMP-2
expression[25]. TNF-α plays an important role in oxidative stress in the
pathogenesis of myocardial remodeling and chronic cardiac
failure. TNF-α induces reactive oxygen species (ROS)
production and is involved in structural changes in
hypertrophy[26]. The stimulation of ROS was reflected by the
increase in the level of malondialdehyde (MDA) and the
activity of oxidant enzyme (XOD) and the decrease in the
level of anti-oxidant enzymes (SOD, GSH-px, and CAT) in
the serum. Oxidative stress is associated with myocardial
contractile dysfunction and structural remodeling. ROS are
also involved in the process of apoptosis of cardio-myocytes
and interstitial fibrosis, both of which contributed to the
development of myocardial structural damage. Our present
study showed that Dex decreased ROS activities in the
serum as well as TNF-α mRNA expression in the myocardium.
We demonstrated that Dex ameliorated CHF induced by
coronary artery ligation in rats. The findings are in
agreement with several reports that Dex protects the heart from
ischemia/reperfusion injury[27,28].
The leptin receptor OB-Rb belongs to the gp130 family
of cytokine receptors and acts primarily through the
activation of the Janus kinase (JAK) family of cytoplasmic tyrosine
kinases, which in turn activate transcription factors of the
signal transducer, and is member of an activator of the
transcription (STAT) family[29]. Leptin stimulates cardiomyocyte
hypertrophy through various intracellular signaling cascades
including the JAK/STAT, p38 mitogen activated protein
kinase (MAPK), extracellular signal regulated kinase (ERK),
and the PI3K/Akt pathway[10,30]. Glucosteroids rapidly
reduce leptin-induced JAK/STAT signaling and a specific
MEK inhibitor PD98059 blocks the inhibitory effects of
glucosteroids on leptin-induced JAK/STAT activation in
Huh7 cells[13], without changing leptin binding to the cells.
Thus, these support our findings that the glucosteroid Dex
could rapidly block leptin signaling pathway, possibly by
significant inhibition of the leptin-induced JAK/STAT
pathway with no effect on the serum levels, and the
upregula-tion of leptin and its receptors in the myocardium. The
cytopro-tective effect by Dex is related to de
novo protein synthesis[31].
Dexamethasone injection and feeding increased plasma
leptin concentrations in dogs. In addition, dexamethasone
administration enhanced the effect of feeding on increases
in plasma leptin concentrations. Daily oral administration of
prednisolone (1 or 2 mg/kg) did not affect plasma leptin
concentrations in dogs[32]. Dex significantly increased OB-Rb
mRNA expression, but leptin inhibited OB-Rb mRNA
expression[33]. This suggests that glucocorticoids as well as leptin
itself had regulatory effects on gene expression of leptin
receptors. Dex stimulates the upregulation of leptin in
combination with either TNF-α[34] or
insulin[35], so, these provide an explanation for improvement of CHF by Dex. Dex
upregulates leptin and its receptors, but suppressed it
signaling pathway. Thus it is likely when other inflammatory
factors contributing to the development of CHF are
suppressed by Dex, the leptin could remain unchanged.
Leptin increases sympathetic
activation[33], generates ROS, and upregulates
TNF-α, MMP-2, and MMP-9 in the myocardium. However, it is a phenomenon of leptin
resistance which is associated with hyperleptinemia with no
biological effects[33]. It remains unclear in biology of leptin and
it is still uncertain whether leptin is a friend or a foe to the
cardiovascular system[18].
In conclusion, hyperleptinemia and the upregulation of
the leptin protein and receptors do not substantially
contribute to CHF. Leptin seems to be only a marker in CHF,
which can be greatly relieved by Dex; however,
hyperleptinemia and the upregulation of the leptin remain unchanged.
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