MOLECULAR MEDICINE REPORTS 5: 923-928, 2012
Abstract. Hydrogen sulfide (H2S) has been recently found to be
an endogenous signaling gasotransmitter. Cardiac hypertrophy
often develops in the course of heart failure. It is unknown
whether or not endogenous H2S protects cardiac hypertrophy.
This study was conducted to examine the effects of H2S on
cardiac hypertrophy and fibrosis induced by abdominal aortic
coarctation and to explore its mechanisms. Male Sprague-
Dawley rats were randomly divided into five groups: normal,
sham, abdominal aortic coarctation (AAC), AAC treated with
enalapril and AAC treated with H2S. One week after surgery,
enalapril and sodium hydrosulfide (NaHS)-treated rats were
fed for 28 consecutive days and sacrificed. After that, the left
ventricle mass index (LVMI), cardiomyocyte size and areas,
collagen volume fraction (CVF) of the rats were measured. In
the AAC rats, the LVMI, the cardiomyocyte size and areas,
and the CVF were all markedly increased while in the H2S
groups they were significantly reduced. H2S decreased the
levels of Ang-II in the heart, but not in plasma. In addition,
H2S also improved the expression of connexin 43 (Cx43). Our
results suggest that H2S can significantly suppress cardiac
hypertrophy and fibrosis induced by overloaded pressure,
possibly by inhibiting the activity of intracardiac Ang-II and
by modifying expression of Cx43.
Cardiac hypertrophy, usually considered as an effective
compensation mechanism, can maintain or even increase
cardiac output. However, in the long term, persistent hyper-
trophy can ultimately progress to cardiac dilatation, decreased
ejection fraction finally leading to heart failure (1). Pathological
changes in ventricular hypertrophy often manifest while the
morphology of cardiomyocytes is altered, such as changes
in cardiomyocyte hypertrophy, interstitial fibrosis (2,3) and
gene expression (4). Clinically, cardiac hypertrophy caused
by various reasons involves different levels of cardiac matrix
changes, especially in hypertensive heart disease (5,6). It has
been reported in both animal and human studies that in left
ventricular hypertrophy (LVH), gene expression alterations in
connexin 43 (Cx43), as well as gap junction disorganization, are
the basis for the triggering and maintainence of arrhythmias
(7-9). Therefore, the regression of cardiac hypertrophy is asso-
ciated with a decreased risk of cardiovascular diseases.
Hydrogen sulfide (H2S) is well known as a noxious gas in
living organisms (10). However, it is increasingly recognized
that like nitric oxide and carbon monoxide, H2S is a member of
the family of ‘gaseous transmitters’. Studies have indicated that,
although in low amounts, H2S can be produced in mammalian
tissues, and is controlled by several pyridoxal-5'-phosphate
(PLP)-dependent enzymes, including cystathionine β-synthase
(CBS), cystathionine γ-lyase (CSE) (10,11), and a newly
identified enzyme, 3-mercaptopyruvate sulfurtransferase
(3-MST) (12,13). Moreover, increasing evidence has shown
that H2S plays important roles in various systems, particularly
in the cardiovascular system (14), regulating vascular tone
(15) and protecting heart from ischemic injury (16). These
various actions highlight the potential important functions
of H2S for modulation of the cardiovascular system. While
cardiac hypertrophy is a major risk factor for the development
of several cardiovascular diseases, it is still unknown whether
endogenous H2S restrains cardiac hypertrophy.
In the present study, an in vivo model of abdominal aortic
coarctation was used. This is the most commonly used method
in cardiac hypertrophy research (17). During this study, we
investigated the effects of H2S administration on cardiac
hypertrophy and fibrosis, levels of Ang-II in cardiac tissues
and plasma, as well as the expression levels of Cx43.
Materials and methods
Materials. The animal experiments complied with the guid-
ance for the Care and Use of Laboratory Animals of Shantou
University Medical College. Adult male Sprague-Dawley
rats (170-190 g) were provided by the Animal Department of
Shantou University Medical College.
Hydrogen sulfide attenuates cardiac hypertrophy and
fibrosis induced by abdominal aortic coarctation in rats
JINGLONG HUANG*, DONGMING WANG*, JINBIN ZHENG, XIANSHENG HUANG and HONG JIN
Department of Cardiology, Medical College, The First Affiliated Hospital of
Shantou University, Shantou, Guangdong 515041, P.R. China
Received October 26, 2011; Accepted December 27, 2011
Correspondence to: Dr Hong Jin, Department of Cardiology,
Medical College of The First Affiliated Hospital of Shantou
University, Shantou, Guangdong 515041, P.R. China
Key words: hydrogen sulfide, cardiac hypertrophy, angiotensin II
HUANG et al: H2S ALLEVIATES CARDIAC HYPERTROPHY AND FIBROSIS
Sodium hydrosulfide (NaHS) was purchased from Sigma
(St. Louis, MO, USA). The Ang-II assay ELISA kit for rat was
purchased from Uscnlife Sciences Co., Ltd. (Wuhan, China).
The rabbit monoclonal antibody against Cx43 was purchased
from Abcam PLC (UK).
Abdominal aortic constriction. Abdominal aortic coarctation
was carried out as described by Phrommintikul et al (17) with
a few modifications. Rats were anesthetized with sodium
pentobarbital (40 mg/kg). Under sterile conditions, the skin
was cut open along the abdominal midline, 4 cm away from
the xiphoid process. The incision was sutured layer after layer
and the animals were injected with penicillin prophylaxis.
Sham-operated animals serving as controls were subjected
to the same surgical procedure except that the aorta was not
Experimental design. Adult male Sprague-Dawley rats,
8-weeks old, were divided randomly into 3 groups as shown in
Table I: i) untreated control (normal, n=10); ii) sham-operated
group (sham, n=10); iii) abdominal aortic coarctation group
(AAC, n=80). One week later, those survival AAC rats were
divided randomly again into three groups: i) abdominal aortic
coarctation only (AAC, n=14); ii) surgery plus enalapril given
by direct gastric gavage (AAC+EN, 5 mg/kg/day, n=14); iii)
surgery plus hydrogen sulfide administered intraperitoneally
(i.p.) (AAC+H2S, 14 µmol/kg/day, n=14). Five weeks after
the surgery, the rats were anesthetized and their hearts were
removed for following analyses.
Determination of cardiac hypertrophy index. The rats were
weighed and then anesthetized with sodium pentobarbital
(40 mg/kg i.p.). The rat heart was removed and rinsed thor-
oughly with cold saline, having washed off the blood. The
atria, great vessels, and the right ventricle along its septal inser-
tion were snipped off. Data were expressed as left ventricular
weight/body weight ratio (mg/g) and were used as an index of
Measurement of endogenous H2S concentration in plasma.
The first 75 µl of plasma was infused into a tube, with the addi-
tion of 250 µl of 1% (w/v) zinc acetate and 425 µl of distilled
water, followed by successive addition of 20 µM N-dimethyl-
p-phenylenediamine sulphate in 7.2 mM HCl (133 µl) and
30 µM FeCl3 in 1.2 mM HCl (133 µl). The test tubes were kept
at room temperature for a 10-min incubation. Then, 250 µl of
10% tricholoacetic acid was added to the reaction mixture, to
remove the protein from the plasma. The OD was measured
with a spectrophotometer at 670 nm.
Histopathological and immunohistochemical analyses. The
ventricles were fixed in 10% formaldehyde and cut into thin
sections (5 µm), followed by staining with hematoxylin and
eosin and picrosirius red in order to determine the degree of
collagen fiber accumulation. The pathological slides were
stained with picrosirius red, and 8 fields were randomly
selected for observation.
Hearts from each group of rats were prepared for immuno-
histochemical analysis. A rabbit monoclonal antibody specific
to Cx43 was applied at 4˚C overnight. After being washed with
PBS, the slides were incubated with biotinylated goat anti-
rabbit IgG (Santa Cruz Biotechnology, Inc., Santa Cruz, CA,
USA) for 30 min at room temperature. The immunoreactivity
was visualized by the streptavidin peroxidase staining method.
Determination of hydroxyproline (Hyp) concentration in cardiac
tissue. Hyp was measured by the modified alkaline hydrolysis
method of Reddy and Enwemeka (18) with modifications. The
absorbance was read at 550 nm using a spectrophotometer.
Figure 1. Concentrations of endogenous hydrogen sulfide in plasma. All results
are expressed as the mean ± standard error. AAC vs. normal, P<0.05; AAC
vs. sham, P<0.05; AAC + EN vs. AAC, P<0.05; AAC + H2S vs. AAC, P<0.05.
Table I. LV weight normalized to body weight (LVW/BW) was used as an index of cardiac mass for the determination of cardiac
Initial BW (g) Final BW (g) Increased BW (g) LVW (mg) LVW/BW (mg/g)
normal 180±10 276±31 96±23 582±62 2.11±0.14
sham 175±3 276±27 101±26 570±69
AAC 173±2 294±25 125±24
AAC+EN 179±9 234±22 54±17
AAC+H2S 179±11 239±16 57±15
Values are indicated as means ± standard error (n=8-11). aP<0.05 vs. normal; bP<0.05 vs. sham; c<0.05 vs. AAC group.
MOLECULAR MEDICINE REPORTS 5: 923-928, 2012
Total collagen content was calculated from the Hyp concentra-
tion assuming that Hyp constitutes 12.5% collagen.
Angiotensin II in plasma and cardiac concentrations. The
concentrations of angiotensin II within the ventricle and
plasma were measured with the method of ELISA. Absorbance
was recorded at 450 nm, and the concentration was calculated
from the generated standard curve of angiotensin II.
Statistical analyses. For comparison among groups, statistical
analyses were performed using one-way analysis of vari-
ance followed by post hoc Tukey's test (SPSS 13.0, Chicago,
IL). All values are expressed as the means ± SD. Prism 4.0
(GraphPad Software, La Jolla, CA) was used to produce
graphs and curve fits. A P-value of <0.05 was taken to indicate
H2S ameliorates left ventricle hypertrophy induced by abdom-
inal aorta coarctation. To determine whether H2S affects
the left ventricle hypertrophy induced by aorta coarctation,
abdominal aortic constriction (AAC groups) was conducted.
Sham-operated animals (sham groups) serving as controls
were subjected to the same surgical procedure except that
the aorta was not constricted. The untreated animals (normal
groups) were also used as controls.
Thirty-five days after the surgery of aortic constriction,
the weight of the left ventricle (LVW) normalized to body
weight (BW) increased significantly. When compared to the
sham group, the ventricular mass index of the model group
increased by 29.6% (Table I), while the weight and quality
index of the left ventricle of the group treated with NaHS
(14 µmol/kg/day) was reduced by 21.0% (P<0.05) and 4.49%
(P<0.05), respectively. The left ventricle weight and quality
index of the left ventricle of the enalapril-treated (5 mg/kg/
day) group decreased by 23.4% (P<0.05) and 6.38% (P<0.05),
respectively. Therefore, these results suggest that H2S amelio-
rates the left ventricle hypertrophy induced by abdominal
Endogenous H2S concentrations in plasma. After surgery,
the concentration of endogenous H2S significantly declined
(Fig. 1). The contents of endogenous H2S of the AAC rats,
which were treated with enalapril, significantly increased,
while the levels of endogenous H2S in the rats which received
NaHS i.p., obviously increased.
H2S improves histological changes in rats treated with abdom-
inal aorta coarctation. Microscopic examination showed that
cardiomyocyte hypertrophy, as evidenced by the minimum
sizes of cells and cardiomyocyte areas, was significantly
increased in AAC rats (Fig. 2A). The cardiomyocyte hyper-
trophy in enalapril rats was lower than that in the model control,
Figure 2. (A) Cross and longitudinal sections of the left ventricle (LV) stained with hematoxylin and eosin. Original magnification (x200). The minimum size of
cardiomyocytes was noted. (B) Collagen deposition. Light micrographs of cardiac fibrosis on LV sections. All sections were stained with picrosirius red stain.
HUANG et al: H2S ALLEVIATES CARDIAC HYPERTROPHY AND FIBROSIS
but was still higher than that in the sham control. Moreover, the
administered H2S obviously decreased the minimum sizes of
cells and areas, when compared to AAC rats.
H2S significantly suppresses development of cardiac fibrosis.
The myocardial fibrosis conditions were measured through
Picro-Sirius red staining. The AAC rats showed a significant
increase in cardiac fibrosis levels when compared to the sham
group (Fig. 2B). For rats in the enalapril or H2S groups, the
collagen densities were significantly lower than those in the
AAC group, but were still higher than those in the sham group.
The Hyp content was significantly increased in the AAC group
(Fig. 3). Treatments with enalapril or H2S attenuated increases
in the Hyp content.
Angiotensin II content in plasma and cardiac tissues. In the
cardiac tissues, the Ang-II concentration markedly increased
in the AAC group when compared to the sham control group
(Fig. 4). The increase in tissues was blocked by enalapril.
H2S could also obviously reduced the high Ang-II contents
subjected to AAC. However, in the plasma, the concentrations
of Ang-II were not significantly different among the groups
(data not shown).
Expression of Cx43 in the myocardial tissues by immunohisto-
chemical analysis. In the AAC group, a significant decrease in
Figure 5. Expression of connexin 43 (Cx43) in myocardial tissues as detected with the method of imunohistochemical analysis. Cx43 is indicated by the black
arrows. Sections from the AAC + EN (abdominal aortic coarctation plus enalapril, 5 mg/kg/day), and AAC + H2S (abdominal aortic coarctation plus hydrogen
sulfide, 14 µmol/kg/day) groups are shown. Original magnification, x200.
Figure 4. Angiotensin II concentration in cardiac tissues was detected
by ELISA. Values are expressed as the mean ± standard. P<0.05, AAC/
AAC + EN/AAC + H2S vs. normal; P<0.05, AAC/AAC + EN/AAC + H2S vs.
sham; P<0.05, AAC + EN/AAC + H2S vs. AAC. EN, enalapril.
Figure 3. Hydroxyproline concentration in the cardiac tissue was measured
with the modified alkaline hydrolysis method. Values are expressed as the
means ± standard error of the measurements. For all statistical comparisons,
n=8-11 animals. P<0.05, AAC/AAC + EN/AAC + H2S vs. normal; P<0.05,
AAC/AAC + EN/AAC + H2S vs. sham; P<0.05, AAC + EN/AAC + H2S vs.
AAC. EN, enalapril.
MOLECULAR MEDICINE REPORTS 5: 923-928, 2012
the density of Cx43 was observed, when compared to the sham
group (Fig. 5). However, enalapril administration ameliorated
expression of Cx43, which was also noted in the H2S group.
This study successfully designed a model of myocardial
hypertrophy through the partial ligation of abdominal aorta of
rats. The presence of myocardial hypertrophy was proven with
typical pathological changes, such as left ventricle hypertrophy
(LVH) (17) and significant thickness of the left ventricle wall
and cardiomyocyte hypertrophy (19). The study results showed
that the myocardial tissue had increased fibrosis and collagen
deposition in the AAC rats. We also found that the Ang-II
expression was upregulated accompanied by cardiac hyper-
trophy in the model group and this is consistent with previous
We discovered that compared with those of the sham
group, the levels of endogenous H2S, a newly recognized gas
transmitter (10,11), were greatly decreased in AAC-induced
LVH rats, suggesting that the endogenous H2S system may
be impaired in the process of cardiac hypertrophy induced
by pressure-overload. In addition, the H2S level was notably
elevated in rats administered enalapril, yet the relevant mecha-
nism is still not clear. The results also revealed that exogenous
administration of H2S via NaHS significantly suppressed the
development of cardiac hypertrophy induced by pressure-
overload, and also greatly downregulated the Ang-II levels in
cardiac tissue. These results suggest that H2S plays a pivotal
role in the development of pressure overload-induced cardiac
hypertrophy. The mechanism may be that H2S, containing a
sulfhydryl-group, interacts with the zinc ion in the active
center of the angiotensin-converting enzyme (ACE) to modu-
late enzyme activity (22) suppressing the Ang-II-induced
cardiac hypertrophy. This is supported by the research of
Laggner et al (23), who found that H2S exerted protection
in the vasculature by reducing the production of Ang-II and
inhibiting bradykinin degradation. However, this experiment
found no difference in the expression of Ang-II in plasma
among the groups, proving that Ang-II in circulation has no
correlation with the development of cardiac hypertrophy.
Moreover, H2S has also been described as an effective antioxi-
dant which increases glutathione production and suppresses
oxidative stress and oxygen species production. Oxygen
species are often increased during cardiac hypertrophy in
response to various stressors (24,25). Therefore, although
the effects of H2S on oxidative stress could not be clarified
in the present study, we could not exclude the possibility that
direct or indirect suppression of oxidative stress might be the
relevant mechanism of H2S to suppress the development of
Myocardial fibrosis is often associated with cardiac hyper-
trophy, with the increase in extracellular matrix, such as collagen
(5,6). Progressive myocardial fibrosis contributes necessarily
to an increase in cardiac muscle stiffness, ultimately leading
to impairment of cardiac function. The results of this study
showed that the rats treated with AAC had obvious cardiac
fibrosis, while treatment with enalapril obvious suppressed the
development of myocardial fibrosis, and this is consistent with
a previous report (26). Our results revealed for the first time
that H2S also markedly prevents the development of cardiac
fibrosis, decreasing the collagen content in the cardiac tissue,
yet the detailed signaling pathway mechanism was not yet
elucidated. Li et al (27) reported that H2S may reduce collagen
accumulation in the pulmonary artery through increasing its
degradation by regulating matrix metalloproteinase (MMPs)
and metalloproteinase (TIMPs) activities. This needs to be
confirmed in future studies on hypertrophied ventricle.
Our study also showed that H2S ameliorated the expres-
sion of Cx43 in cardiac tissue. Cx43 is the principal connexin
in the mammalian ventricle and has been proven to have a
close association with cardiac hypotrophy or arrhythmia (28).
Roell et al (28) pointed out that engraftment of Cx43-expressing
myocytes has the potential of reducing life-threatening post-
infarct arrhythmias through the augmentation of intercellular
electrical conduction. We also found that the expression of
Cx43 was altered in the LVH rats, representing a reduction
in the number of step-to-step junctions, which was consistent
with previous research (29). Changes in Cx43 within the
hypertrophic ventricles were rather complicated, including
the synthesis, metabolism, redistribution, and mRNA expres-
sion of Cx43 (30). Research has demonstrated that Ang-II,
endothelin-I, and transforming growth factor-β stimulate the
expression of Cx43 (31). Our findings indicate that endogenous
H2S may play an important role in regulating heart function
In this study we investigated the chronic effects of exogenous
H2S and proposed novel protective effects of H2S on cardiac
hypertrophy and fibrosis. The limitation is that we only observed
the ameliorating- effects of H2S on cardiac hypertrophy and
fibrosis, but did not investigated the direct regulating effects of
H2S on ACE activity and mRNA expression. Neither did we
observe the oxidative stress changes in myocytes, which will be
the future research direction of our team.
In summary, our results demonstrated that H2S has some
beneficial effects on deferring or suppressing the development
of left ventricle hypertrophy and cardiac fibrosis induced by
abdominal aorta coarctation in rats. The mechanisms may be
at least partially related to H2S, regarding its modulation of
intracardiac renin-angiotensin system activity and Cx43.
This study was supported by the Foundation for Natural
Science of Guangdong Province, China (no. 6033503).
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