Research Article

Effect of carvedilol on cardiomyocyte apoptosis in a rat model

of myocardial infarction: A role for toll-like receptor 4
Jianhua Zhang, Qingwei Liu, Yan Xu, Ying Huang, Changhao Wu1

ABSTRACT
Objectives: Toll-like receptor 4 (TLR4) is crucial in cardiomyocyte apoptosis induced
by myocardial infarction (MI) and carvedilol has been reported to have anti-apoptotic
Department of Cardiology, effects. We hypothesized that the effects of this agent are in part mediated through
The First Affiliated Hospital of TLR4 signaling pathways.
Anhui Medical University, Hefei Materials and Methods: A total of 48 rats were randomized to the following groups before
230022, PR China, surgery: sham-operated group (n = 8), MI group (n = 10) and three carvedilol-treatment
1
Faculty of Health and Medical groups (n = 30, 2 mg/kg, 10 mg/kg and 30 mg/kg). Sham and MI groups were given vehicle
Sciences, Division of Biochemistry and carvedilol groups received different dose carvedilol, by direct gastric gavage for 7 days.
and Physiology, University of On the 4th day of drug or vehicle administration, MI model was produced by ligating the left
Surrey, Guildford, GU2 7XH, UK
anterior descending coronary artery. On day 3 after MI, apoptosis was assessed by TdT-UTP
nick-end assay; the levels of expression of Bax, Bcl-2, TLR4 and nuclear factor-κB (NF-κB)
Received: 21-03-2012
Revised: 09-09-2012 in infarcted myocardium were analyzed by immunohistochemistry.
Accepted: 30-06-2013 Results: Carvedilol ameliorated MI-induced apoptosis in a dose-dependent manner.
In parallel, carvedilol also decreased the ratio of Bax to Bcl-2, the expression of TLR4
Correspondence to: and NF-κB induced by MI. The extent of apoptosis and Bax-Bcl-2 ratio was strongly
Prof. Yan Xu, correlated with the TLR4 levels.
E-mail: anyi_xuyan@hotmail.com Conclusion: This study suggests that the short-term administration of carvedilol can
significantly alleviate cardiomyocyte apoptosis in the infarcted myocardium probably
by inhibiting the excessive expression of TLR4 and NF-κB induced by infarction.

KEY WORDS: Apoptosis, carvedilol, myocardial infarction, toll-like receptor 4

Introduction quantitative study reported that apoptotic and necrotic myocyte

Apoptosis is a distinct form of cell death characterized by a
series of typical morphological events, such as shrinkage of the
cell, fragmentation into membrane-bound apoptotic bodies and
rapid phagocytosis into the neighboring cells without induction
of an inflammatory response. Cardiomyocyte apoptosis is an
important event after acute myocardial infarction (AMI) and may
be responsible for a significant portion of myocyte death during
the acute ischemic stage.[1] In the initial 1-7 days of myocardial
infarction (MI), apoptotic myocyte cell death precedes cell
necrosis and is the major determinant of infarct size.[2] A
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DOI: 10.4103/0253-7613.117729
cell death were both independent contributing variables of
infarct size, but apoptosis accounted for 86% of the total loss
of myocytes and necrosis for only 14%.[3] The loss of cardiac
myocytes is one of the mechanisms involved in MI-related
heart failure; inhibition of cardiomyocyte apoptosis following
MI may therefore improve left ventricular (LV) remodeling and
cardiac function.[4]
Toll-like receptor 4 (TLR4), a class of pattern recognition
receptors, has recently emerged as a key player in inflammation
and innate immunity, including innate immune responses,
antigen presentation and more importantly cytokine gene
expressions.[5] Conventional TLR4 signaling recognizes the
ligands, activates nuclear factor-κB (NF-κB) pathway and is
sufficient to trigger the inflammatory response.[6] One main
function of TLR4 in the non-immune system is to regulate
apoptosis. Kim et al. reported that TLR4-NF-κB pathway was
involved in cardiac myocytes apoptosis.[7] TLR4-NF-κB pathways
were markedly activated in failing and ischemic myocardium.[8]
Conversely TLR4 deficiency led to improved survival after MI
mediated by attenuated apoptosis and LV remodeling.[9]

458 Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5

 Zhang, et al.: Carvedilol on apoptosis: Role of TLR4
Carvedilol is a non-selective α1- and β-receptor blocker
initially used in the treatment of hypertension. In addition to
its antihypertensive property, carvedilol has been shown to
significantly reduce morbidity and mortality in heart failure and
post-AMI patients.[10,11] Yue et al. first reported that the protective
effects of carvedilol on the ischemic myocardium involved an
inhibition of apoptosis of cardiomyocytes in an experimental
model of ischemia/reperfusion.[12] Carvedilol has also been shown
to inhibit cardiomyocyte apoptosis in vitro.[13] Schwarz et al. have
further demonstrated that the antiapoptotic effects of carvedilol
are independent of its β-adrenoceptor blocking effects.[14]
However, whether the TLR4 signaling pathway is involved in
the antiapoptotic effect of carvedilol has never been examined.
In the present study, we hypothesized that the beneficial
effects of carvedilol on AMI-induced apoptosis could be related
to the down-regulation of TLR4-mediated signaling activity.
Materials and Methods
Experimental Model
Rat MI model was generated by ligating the left anterior
descending (LAD) coronary artery according to a previously
described method. [15] Briefly, after being anesthetized by
intraperitoneal injection of ethyl carbamate (1.0 g/kg), all
animals underwent endotracheal intubation. Mechanical
ventilation was provided with room air at 60-70 breath/
min using a rodent respirator (Taimeng Company, Chengdu,
China). A standard lead-II electrocardiogram was recorded via
subcutaneous stainless steel electrodes. Left thoracotomy was
performed to expose the heart at the fifth intercostal space;
LAD was ligated with a 5-0 silk suture. Ischemia was confirmed
by the elevation of ST segment in the electrocardiogram and
cardiac cyanosis. Following these surgical procedures, rats were
allowed to stabilize for 15 min and then the thoracic cavity was
closed. The sham-operated rats underwent the same operative
procedure, but the suture was loosely tied to avoid coronary
artery occlusion.
A total of 48 rats were randomized to the following groups
before surgery: sham-operated group (n = 8), MI group
(n = 10), 2 mg/kg carvedilol-treatment group (n = 10), 10 mg/
kg carvedilol-treatment group (n = 10), 30 mg/kg carvedilol-
treatment group (n = 10). Sham and MI groups were given
vehicle and carvedilol groups received different dose carvedilol,
by direct gastric gavage for 7 days. On the 4th day of drug or
vehicle administration, forty rats (except Sham group) were
rendered MI by ligation of LAD.
All animal experiments were performed with permission
from the Medical Ethics Committee at Anhui Medical University
and followed the protocol outlined in the Guide for the Care
and Use of Laboratory Animals published by the US National
Institutes of Health (Publication No. 85-23, revised 1996).
Histological Preparation
Three days after MI, the rats were euthanized with an
overdose of anesthetic. The heart was excised and placed on ice
and the myocardium was flushed with ice-cold Krebs buffer. The
left ventricle was sliced into segments along the short-axis. One
segment from the mid-ventricle was fixed in cold 10% formalin
solution and embedded in paraffin for in situ TdT-UTP nick-end
labeling (TUNEL) and immunohistochemistry.
TUNEL Analysis
Apoptotic cardiomyocytes were detected with TUNEL assay.
Briefly, myocardial tissue sections (4 µm) were incubated with
proteinase K for 5 min at 37°C and then washed with tris-
buffered saline (TBS). Endogenous peroxidase was inactivated
by treatment with 0.3% H2O2 for 5 min at room temperature
and sections were incubated with the labeling buffer containing
TdT, Mn+, biotinylated-deoxyuridine 5-triphosphate at 37°C
for 70 min. Sections were then incubated with streptavidin-
horseradish peroxidase for 10 min. Freshly prepared
diaminobenzidine (DAB) solution was added for coloration.
Finally, the specimens were counter-stained with hematoxylin,
washed with TBS and the signals were visualized. The number
of apoptotic cardiomyocytes and their percentage of total
cardiomyocytes were counted with the use of a microscope.
Cardiomyocytes from at least three randomly selected sections
per animal were evaluated immunohistochemically for these
variables. The number of TUNEL-positive cells was calculated
as cells per area of heart tissue at 400-fold magnification. The
percentage of TUNEL-positive cells was calculated as a percentage
of total cells viewed in five randomly selected fields for each group.
Immunohistochemistry
The hearts fixed in 10% phosphate-buffered formaldehyde
were routinely processed and paraffin-embedded. Tissue
sections (4 µm) mounted on poly-L-lysine-coated glass slides
were deparaffinized with xylene. After washing with phosphate-
buffered saline (PBS) solution, the sections were treated with
0.3% H2O2/methanol and heated for 5 min in 10 mmol/L citrate
buffer at 95°C. The normal goat serum-blocking solution was
added the sections incubated at room temperature for 30 min
and the extra liquid removed. The primary antibodies against
TLR4 (1:150, Santa Cruz), NF-κB p50 (1:200, Santa Cruz), Bax
(1:100, Santa Cruz), Bcl-2 (1:300, Santa Cruz) were then added
and the slides incubated over night at 4°C. Negative controls
were included with the omission of the primary antibodies. After
washing with PBS solution, the sections were incubated with the
secondary antibody (goat anti-mouse immunoglobulin G (Zymed
Laboratories) 37°C for 30 min. Streptomycete antibiotin-
peroxidase solution was added and then freshly prepared DAB
solution for coloration. Sections were counterstained with
hematoxylin and mounted for light microscopy. The optical
density was evaluated with computer-assisted image analysis
(Image-Pro Plus 6.0, Media Cybernetics, Silver Springs, MD,
USA). Five fields were randomly chosen for each slide. The
value of mean optical density was calculated. The assays were
performed in a blind manner.
Statistical Analysis
All data are expressed as mean ± standard deviation (SD)
statistical analysis was performed with the statistical package
for the social sciences 13.0. One-way analysis of variance
was used for comparisons between the groups. P < 0.05 was
considered to be statistically significant.
Results
Effect of Carvedilol on Cardiac Myocyte Apoptosis
The occurrence of apoptosis was indicated by the
cardiomyocyte nuclei with deoxyribonucleic acid fragmentation
detected by TUNEL. TUNEL-positive myocytes were barely
Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5 459
 Zhang, et al.: Carvedilol on apoptosis: Role of TLR4

detectable in Sham [Figure 1a and f], but significant increase
in MI [32.50 ± 4.5%, Figure 1b and f, P < 0.05 vs. Sham]. In
contrast to MI, carvedilol-treatment resulted in a significant
reduction in the number of TUNEL-positive myocyte nuclei
[Figure 1c-f] (P < 0.05 vs. MI group). The maximal inhibition
ratio was 36% (seen in Car 30 mg/kg group).
Effect of Carvedilol on the Expression of Bax, Bcl-2 and the
Ratio of Bax to Bcl-2
Immunoreactivity of Bax and Bcl-2 was yellow-brown
reactive product located in the cytoplasm of the cardiomyocytes.
As shown in Figure 2, there was limited expression of Bax
in Sham group [Figure 2a and f]. The expression of Bax was
significantly increased in MI group [Figure 2b and f] (P < 0.05
vs. Sham group). Carvedilol-treatment [Figure 2c-f] attenuated
the increase (P < 0.05). Figure 3 shows that the expression of
Bcl-2 was increased in MI and the three Car groups (P < 0.05
vs. Sham), although the difference between MI and carvedilol-
treatment groups was not statistically significant. The ratio of
Bax to Bcl-2, a better apoptotic index than the two proteins
considered separately, was increased in MI group (1.57)
compared with Sham group (0.89), but normalized by carvedilol
treatment (1.11 for 2 mg/kg, 1.00 for 10 mg/kg and 0.88 for
30 mg/kg).
Effect of Carvedilol on the Expression of TLR4
TLR4 positive expression, which manifested as a pervasive
brown-yellow color in the myocardial cells, was found in the
myocardial tissue sampled from all the five groups. There
was a low-level of expression of TLR4 protein in Sham group
[Figure 4a and f]. The expression of TLR4 protein in MI group
[Figure 4b and f] was significantly higher (P < 0.05 for all MI
groups vs. Sham). Carvedilol-treatment [2, 10 and 30 mg/kg,
Figure 4c-f] consistently decreased the excessive expression
of TLR4 protein induced by MI (P < 0.05 versus. MI group).
The relationship between TLR4 and apoptosis was further
analyzed. Changes to the level of TLR4 were closely correlated
to the extent of MI-induced cardiomyocytes apoptosis as well
as the ratio of Bax to Bcl-2 as the dose of carvedilol varied
[Figure 5].

Figure 1: Apoptotic cells in the infarcted area assessed by immunostaining of TdT-UTP nick-end labeling-positive cells (brown) (×400). (a) Sham;
(b) Myocardial infarction (MI); (c) Car 2 mg/kg; (d) Car 10 mg/kg; (e) Car 30 mg/kg; (f) Data of quantitative analysis are expressed as mean ±
standard deviation. *P < 0.05 versus Sham, #P < 0.05 versus MI

a b c

d e f

Figure 2: Immunohistochemical staining of Bax in myocardial sections (×400). (a) Sham; (b) Myocardial infarction (MI); (c) Car 2 mg/kg; (d) Car
10 mg/kg; (e) Car 30 mg/kg; (f) Data of quantitative analysis are expressed as mean ± standard deviation. *P < 0.05 versus Sham, #P < 0.05
versus MI, †P < 0.05 versus Car 2 mg/kg

a b c

d e f

460 Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5

 Zhang, et al.: Carvedilol on apoptosis: Role of TLR4

Figure 3: Immunohistochemical staining of Bcl-2 in myocardial sections (×400). (a) Sham; (b) Myocardial infarction; (c) Car 2 mg/kg; (d) Car 10
mg/kg; (e) Car 30 mg/kg; (f) Data of quantitative analysis are expressed as mean ± standard deviation. *P < 0.05 versus Sham

a b c

d e f

Figure 4: Effect on the expression of toll-like receptor 4 in different groups measured by immunohistochemistry (×400). (a) Sham; (b) Myocardial
infarction (MI); (c) Car 2 mg/kg; (d) Car 10 mg/kg; (e) Car 30 mg/kg; (f) Data of quantitative analysis are expressed as mean ± standard deviation.
*P < 0.05 versus Sham; #P < 0.05 versus MI

a b c

d e f

Figure 5: Correlation between toll-like receptor 4 and the apopototic
variables. (a) Apoptotic cardiomyocytes; (b) Bax/Bcl-2 ratio
a b
Effect of Carvedilol on the Expression of NF-κB p50
The expression of NF-κB p50 3 days after MI was measured
by immunohistochemistry [Figure 6]. Four days after MI, marked
increase of p50 was observed, mostly in the nuclear staining
of the infarcted region. Carvedilol treatment inhibited NF-kB
subunit p50 expression induced by MI (P < 0.05), especially in
Car 30 mg/kg group (P < 0.05 vs. Car 2 mg/kg).
Discussion
In the present study, we have investigated the protective
effect of carvedilol on cardiomyocyte apoptosis and the possible
mechanisms in a rat model of MI closely mimicking human
anatomy physiology. The main results of the present work
are: (1) Short-term administration of carvedilol significantly
inhibited cardiomyocyte apoptosis in infarcted region 3 days
after MI. (2) In parallel to the effect on apoptosis, carvedilol
treatment alleviated the over-expression of TLR4 and NF-κB
proteins induced by MI.
Occlusion of a major coronary artery in the rat is a
well-characterized animal model of acute MI and its chronic
sequelae, such as chronic heart failure. Cardiomyocyte
apoptosis occurs in MI and importantly contributes to
its pathological progression. In this model, apoptotic
cardiomyocytes were seen in the central ischemic areas in
the acute phase of infarction.[2] In the chronic stage of MI as

Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5 461

 Zhang, et al.: Carvedilol on apoptosis: Role of TLR4
Figure 6: Effect on the expression of nuclear factor-κB p50 in different groups examined by immunohistochemistry (×400). (a) Sham; (b) Myocardial
infarction (MI); (c) Car 2 mg/kg; (d) Car 10 mg/kg; (e) Car 30 mg/kg; (f) Data of quantitative analysis are expressed as mean ± standard deviation.
*P < 0.05 versus Sham, #P < 0.05 versus MI, †P < 0.05 versus Car 2 mg/kg
a b
d e
much as 54% of the TUNEL-positive cardiomyocytes appeared
in the noninfarcted tissue; this was correlated with the degree
of ventricular enlargement and remodeling, resulting in chronic
heart failure.[16] A recent clinical study suggests that carvedilol
may be superior to other β-adrenoceptor blockers in the
improvement of heart failure and one possible mechanism
underlying this particular beneficial effect could be regulating
apoptosis. [10] In animal experiments, carvedilol inhibited
necrosis and apoptosis of ischemic myocardial cells, leading
to improved post-MI remodeling.[14,17] Bax and Bcl-2, the two
main members of the apoptosis family, critically influence the
permeability of the mitochondrial membrane and regulate
apoptosis.[18] Bax is a pore-forming cytoplasmic protein and
in response to an enhanced oxidative stress, translocates to
the outer mitochondrial membrane, alters its permeability and
induces cytochrome c loss from the intermembrane space of
the mitochondria into the cytosol. The anti-apoptotic Bcl-2,
on the other hand, acts on the outer mitochondrial membrane
and stabilizes the membrane permeability, thus preserving
mitochondrial integrity and suppressing the cytochrome
c release. The ratio of Bax to Bcl-2 may therefore better
predict the apoptotic fate of the cell.[19] The present study
showed that the administration with carvedilol decreased
TUNEL-positive cardiomyocytes and inhibited the increase of
Bax:Bcl-2 ratio induced by MI. This suggests that the short-
term administration of carvedilol can significantly suppress
the apoptosis and affect its regulatory proteins in the acute
stage of MI. The clinical implication is that carvedilol may
act early to bring a beneficial effect to the cardiac function
following MI.
In recent years, increasing evidence suggests that
inflammatory cytokines are involved in MI. [20] TLR4, the
first Toll receptor identified in mammal, manifests itself in
all cell types and plays an important role in regulating the
inflammatory reaction. Recent studies have suggested that
TLR4 expression both at mRNA and protein levels is increased
in MI.[8] TLR4-mediated pathways played a key role in triggering
the post-infarction inflammatory response by activating the
NF-κB system and in TLR4 knockout mice, the activation of
462 Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5
c
f
NF-κB induced in MI was markedly inhibited.[21,22] An important
function of TLR4 in the non-immune system is anti-apoptosis.
In contrast to wild type-MI mice, the infarcted area of knock-
out -MI mice displayed a significantly decreased content of
TUNEL-positive apoptotic cells induced by MI (approximately
73%).[9,23] More recently, TLR4 blocking antibody was also
found to inhibit the apoptosis of isolated cardiac myocytes.[24]
In the present study, the expression of TLR4 and activity of
NF-κB in the infarction region was significantly increased in
MI group. Short-term administration of carvedilol significantly
inhibited the expression of TLR4 and the activity of NF-κB.
Furthermore, changes to MI-induced TLR4 expression largely
mirrored the effects on apoptotic parameters with varying
carvedilol doses. A strong correlation of TLR4 with apoptosis
and its regulatory proteins was indicated. These data suggest
that the anti-apoptotic effect of carvedilol may be associated
with an inhibition of the excessive expression of TLR4-NF-κB
pathway.
Conclusion
The results suggest that the short-term administration of
carvedilol significantly reduces cardiomyocyte apoptosis in
the infarcted area probably via an inhibition of the excessive
expression of TLR4 and NF-κB induced by MI.
Acknowledgments
We wish to thank Anhui Provincial Natural Science Foundation
(number: 070413103) and by Anhui Provincial Bureau of Education
Natural Science Foundation (number: KJ2009A036Z), PR China for
supporting this work.
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Cite this article as: Zhang J, Liu Q, Xu Y, Huang Y, Wu C. Effect of carvedilol
on cardiomyocyte apoptosis in a rat model of myocardial infarction: A role for
toll-like receptor 4. Indian J Pharmacol 2013;45:458-63.
Source of Support: This work was supported by Anhui Provincial
Natural Science Foundation (number: 070413103) and by Anhui
Provincial Bureau of Education Natural Science Foundation (number:
KJ2009A036Z), PR China, Conflict of Interest: No.
Indian Journal of Pharmacology | October 2013 | Vol 45 | Issue 5 463
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