Vol. 277, Issue 4, H1553-H1561, October 1999
Emotional stress induces immediate-early gene expression in
rat heart via activation of 
- and 
-adrenoceptors
Takashi
Ueyama1,
Ken-Ichi
Yoshida2, and
Emiko
Senba1
1 Department of Anatomy and
Neurobiology, Wakayama Medical College, Wakayama 641-8509; and
2 Department of Legal Medicine,
Yamaguchi University School of Medicine, Ube 755-0001, Japan
 |
ABSTRACT |
We have studied the adrenergic mechanisms of
immediate-early gene (IEG) induction in the discrete types of cardiac
cells with the use of in situ hybridization histochemistry in an
immobilization-stress model in conscious rats. Expression of
c-fos,
fos B,
c-jun, jun B, NGFI-A, and
NGFI-B mRNA was rapidly upregulated in the endothelial, myocardial, and
smooth muscle cells of coronary vessels by 15-45 min after the
onset of immobilization. Simultaneous blockade of both 
- and
-adrenoceptors completely abolished expression of IEGs in these
cardiac cells. Application of an -agonist or -agonist alone to
the perfused rat heart under constant pressure elicited the
upregulation of IEGs in a fashion similar to that of emotional stress.
These data suggest that activation of either - or -adrenoceptor is sufficient to evoke expression of these genes and that there may be
cross talk in signal transduction downstream from - and -adrenoceptors in cardiac cells.
catecholamine; endothelial cells; cardiac myocytes; coronary
artery; immobilization stress
| |
INTRODUCTION |
PSYCHOSOCIAL FACTORS are considered to be etiologic
factors in cardiac disorders, including ischemic heart disease,
arrhythmia, and sudden cardiac death (7). In particular, the
sympathoadrenal medullary system plays a key role in the manifestation
of cardiovascular stress responses (30, 43). Norepinephrine and
epinephrine directly affect the heart via specific cardiac
adrenoceptors, increasing heart rate and myocardial oxygen demand. They
also affect the heart indirectly by increasing systemic blood pressure and by reducing the coronary blood flow via contraction of vascular smooth muscle cells and aggregation of platelets (16). These complex
interactions make it difficult to distinguish the direct cardiac action
of catecholamines from their indirect actions. Our main goal in this
study was to examine how cardiac adrenoceptors mediate the molecular
changes that follow emotional stress.
Immediate-early genes (IEGs), such as
c-fos and
c-jun, are rapidly induced in various
kinds of cells in response to stimuli such as growth factors,
transmitters, high temperature, ultraviolet irradiation, toxic
chemicals, or ischemia-reperfusion (28, 31). Mechanical stretch
(32), activation of the renin-angiotensin system (23), adrenoceptors
(10, 12), or ischemia-reperfusion (24, 25) can also induce IEGs
in the cardiac cells. The protein products of
c-fos and
c-jun mRNA, c-Fos and c-Jun, form AP-1
complex (c-Fos/c-Jun or c-Jun/c-Jun dimer), thereby upregulating the
synthesis of other proteins such as atrial natriuretic peptide (14) and -actin (4). In the heart, this pathway is involved in a hypertrophic response to stretch, angiotensin, and catecholamines (44, 46).
Immobilization (IMO) stress of rats is a useful model of emotional
stress because it induces activation of the sympathoadrenal medullary
system, the hypothalamopituitary-adrenocortical axis, and elevation of
blood pressure and heart rate (15, 27). In situ hybridization analysis
has a great advantage over Northern analysis because potential changes
can be localized in specific types of cardiac cells. Using this
technique and the IMO model, we have shown that emotional stress
induces differential spatial and temporal expression of IEGs in various
kinds of tissues (35), including the rat heart (41). However, the
underlying mechanisms of IEG induction in different cardiac cells
remain unknown, because increased afterload,
ischemia-reperfusion, and activation of adrenoceptors may be
independently or synergistically involved.
To examine the mechanism of IEGs induction, we focused on the effect of
- and/or -adrenergic blockers in comparison with a
calcium-channel blocker and other cardioactive drugs. The first experiment indicated that direct activation of - or
-adrenoceptors was essential to induce expression of IEGs. To
confirm this finding, we further examined IEG expression in the
isolated, perfused heart model after infusion of - and/or
-adrenergic agonists in the absence of emotional stress,
ischemia, and pressure overload.
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MATERIALS AND METHODS |
Tissue preparation.
Male Wistar rats, 6 wk old, were purchased from Kiwa Laboratory Animals
(Wakayama, Japan) and housed in a temperature-controlled environment.
Experiments were performed after the rats had been allowed free access
to food and water for 1 wk. The animals were restrained by securing
them on their back to a board with the use of adhesive tape (IMO) (15,
27). Four nonrestrained animals served as controls. The rats were
decapitated under ether anesthesia at 15, 30, 45, 60, or 120 min after
the start of IMO (n = 4 at each time
point). The hearts were rapidly removed and immediately frozen, using
powdered dry ice, within 1 min after decapitation. All animal
manipulations were approved by the Wakayama Medical College Animal Care
and Use Committee. The frozen tissues were stored at 
80°C
until sectioned.
Pharmacological treatment.
An 1-adrenoceptor blocker,
prazosin hydrochloride (Sigma, St. Louis, MO), a
1-adrenoceptor blocker,
metoprolol tartrate (Sigma), an /-adrenoceptor blocker,
amosulalol hydrochloride (a gift from Yamanouchi Pharmaceutical, Tokyo,
Japan), a calcium-channel blocker, diltiazem hydrochloride (Sigma), a
class Ib antiarrhythmic drug, lidocaine hydrochloride (Sigma), and a
potent vasodilating agent, nitroglycerin (Millisrol; Nihon Kayaku,
Kyoto, Japan) were used. The animals were fasted for 24 h before the
experiments. Each drug dissolved in physiological saline was
administered before IMO: prazosin (1 mg/kg po, 45 min before),
metoprolol (10 mg/kg ip, 10 min before), amosulalol (50 mg/kg po, 60 min before), diltiazem (50 mg/kg ip, 10 min before), lidocaine (2 mg/kg
ip, 10 min before), and nitroglycerin (100 µg/kg ip, 10 min before).
After drugs were administered, the rats were exposed to IMO for 20 min
and then hearts were rapidly removed and immediately frozen, using
powdered dry ice, within 1 min after decapitation
(n = 4 for each drug). Controls for
the drug studies were treated with the same dosage and schedule of drug
administration before decapitation; however, they were not subjected to
IMO stress (n = 4 for each drug). Drug dosages were chosen on the basis of efficacy in reducing blood pressure
in experimental hypertensive rat models (3, 11, 13, 17) or
protecting against ischemic arrhythmias induced by coronary
artery occlusion (2).
Perfusion procedure.
Hearts of Wistar rats weighing 200-250 g were perfused by the
Langendorff procedure. The hearts were perfused initially for 10-20 min with a modified Krebs-Henseleit solution
[comprising (in mM) 124 NaCl, 24.9 NaHCO3, 1.2 KH2PO4,
4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 5.5 glucose, and 2.0 sodium
pyruvate, pH 7.4, gassed with 95%
O2-5%
CO2, 37°C] at a constant
pressure of 80 cmH2O. An
1-agonist, phenylephrine (10 µM; n = 4), a -agonist,
isoproterenol (0.1 µM; n = 4), or a
combination of these two drugs (n = 4)
was added to the perfusion medium (39). After 15 min of drug
administration or drug-free perfusion
(n = 4), the hearts were immediately
frozen using powdered dry ice.
In situ hybridization histochemistry.
Frozen sections 10 µm in thickness were cut in a cryostat and
thaw-mounted onto silane-coated slides. They were fixed in 4% paraformaldehyde-0.1 M phosphate buffer, pH 7.4, for 15 min at room
temperature, rinsed in 2× standard saline citrate (SSC), and
dehydrated by being passed through 70%, 80%, 90%, 95%, and 100%
ethanol. After they were dried, the slides were stored at 80°C until hybridized.
Oligonucleotide probes were synthesized using an Applied Biosystem 381A
DNA synthesizer and then purified using HPLC. The probe sequences
complementary to the nucleotides spanning amino acids were as follows:
c-fos (45-mer), 1-15 (6);
fos B (42-mer), 93-107 (45);
c-jun (60-mer), 309-328 (1);
jun B (60 mer), 325-344 (34);
jun D (60-mer), 322-341 (33);
NGFI-A (45-mer), 2-16 (21); and NGFI-B (45-mer), 1-15
(22). A computer-assisted homology search revealed no
identical sequences in any genes in the database (GenBank). The probes
were labeled with 35S-labeled dATP
using terminal deoxynucleotidyltransferase (Toyobo, Osaka, Japan). The
specific activity of each probe was 5-10 × 108
counts · min
1 · µg1.
Excess (50×) amounts of cold probes completely eliminated the hybridization signals for the respective mRNAs. Sections were hybridized overnight at 37°C in 100 µl of buffer containing
4× SSC, 50% formamide, 0.12 M phosphate, 1× Denhardt's
solution, 0.2% SDS, 250 µg/ml yeast tRNA, 10% dextran sulfate, and
100 mM dithiothreitol with 106
counts/min of labeled probe per slide. After hybridization, the sections were washed four times for 20 min at 55°C in 1× SSC, immersed briefly in distilled water and dehydrated with a graded ethanol series, and then dried. Film autoradiography and estimation of
radioactivity were performed using the Bioimaging analyzer BAS2000
(Fuji Film, Tokyo, Japan). We averaged the radioactivity for each
animal and subtracted the background, which was assumed to be
equivalent to the amount of signal generated by 50× excess cold
probe. Data were means ± SD normalized to the value for the untreated control group. The effects of stress and
treatment with each drug were evaluated using ANOVA. Post hoc tests
were performed, and the data were analyzed using the Fishers protected
least significant difference test with the StatView computer program.
Next, the slides were coated with Ilford k-5 emulsion diluted 1:2 with
water for autoradiography and then exposed for 4 wk at 4°C. Slides
were developed in D-19 (Kodak), and the sections were counterstained with hematoxylin-eosin for morphological examination. All slides for
the same probes were processed simultaneously.
| |
RESULTS |
Signals for IEG mRNAs were not observed in prestress control heart
tissues. IMO induced the de novo mRNA expression of IEGs from 15 min
(Fig. 1). Signals for IEG mRNAs were
transiently observed from 15 to 45 min and returned to the control
level at 60 min under IMO stress (Fig. 1). As shown in Fig.
2, signals for
c-fos and NGFI-A mRNAs were strongly
expressed in the myocardium in the area surrounding the left
ventricular cavities. These signals were also observed in the smooth
muscle cells of coronary arteries (Fig. 2). Strong signals were also
observed in the right ventricular wall and papillary muscles, but there
were few signals in the atria (data not shown). The strongest signals
were especially observed in the endothelial cells (Fig.
3), and moderate signals were distributed on the
myocardiac cells. Signals for fos B,
c-jun, jun B, and NGFI-B mRNAs were moderate
or weak. The signal for jun D mRNAs
was very weak.
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Fig. 1.
Film autoradiography showing time course for expression of
c-fos,
fos B,
c-jun,
jun B,
jun D, NGFI-A and NGFI-B mRNA in
heart. Axial sections of heart were taken from a nonstressed animal
(time 0) and animals subjected to
immobilization stress for 15, 30, 45, 60, and 120 min. Note that
immobilization stress induced c-fos,
fos B,
c-jun, NGFI-A, and NGFI-B mRNAs from
15 min. Levels of these mRNAs reached a maximum after 30 min of stress
and decreased after 45 min.
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Fig. 2.
Dark-field photomicrographs showing signals for
c-fos
(A),
fos B
(B),
c-jun
(C),
jun B
(D),
jun D
(E), NGFI-A
(F), and NGFI-B mRNA
(G) in heart. LV; left ventricle.
Note that strong signals for these immediate-early genes (IEGs) were
observed in myocardium localized to the area surrounding LV cavities.
These signals were also observed in smooth muscle cells of coronary
arteries (arrowheads). Bar, 600 µm.
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Fig. 3.
Bright-field (A,
C, E,
G, and
I) and dark-field photomicrographs
(B,
D, F,
H, and
J) showing signals for
c-fos mRNA in heart taken from an
untreated control rat (Con; A and
B) and heart perfused with
phenylephrine (a; C and
D), isoproterenol (;
E and
F), or phenylephrine plus
isoproterenol (a; G and
H), where a = . Heart shown in
I and
J were taken from a rat after 30 min
of immobilization (IMO) stress. Note that the strongest signals were
especially observed on endothelial cells (arrowheads) and moderate
signals were distributed on myocardiac cells. Bar, 60 µm.
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Treatment of rats with a number of cardioactive agents, including
nitroglycerin, diltiazem, lidocaine, prazosin, or metoprolol, did not
by itself induce the expression of
c-fos (Fig. 4),
c-jun, or NGFI-A mRNA in the rat heart
(data not shown). Pretreatment with nitroglycerin, diltiazem,
lidocaine, prazosin, or metoprolol did not suppress the upregulation of
IEGs elicited by stress; however, pretreatment with prazosin and
metoprolol combined or with the /-adrenoceptor blocker amosulalol
did abolish completely the stress-induced expression of
c-fos mRNA (Fig. 4). The
stress-induced expression of c-jun and
NGFI-A mRNAs was also completely blocked by pretreatment with - and
-blockade (data not shown). Semiquantitative analysis of these mRNA
levels is shown in Fig. 5. There were no significant
differences in relative c-fos and
NGFI-A mRNA levels among IMO (4.70 ± 1.58 and 6.66 ± 2.62, means ± SD normalized to control value;
n = 4) or among IMO after pretreatment
with nitroglycerin (4.67 ± 0.98 and 6.16 ± 1.64),
diltiazem (4.06 ± 0.65 and 5.73 ± 2.17), lidocaine (4.35 ± 0.99 and 5.04 ± 1.46), prazosin (4.39 ± 0.95 and 5.56 ± 1.50), or metoprolol (4.27 ± 0.15 and 6.72 ± 1.34). However,
IMO after pretreatment with both prazosin and metoprolol combined (0.95 ± 0.15 and 1.09 ± 0.18) or with amosulalol (1.06 ± 0.12 and
1.20 ± 0.20) did significantly attenuate the upregulation of
c-fos and NGFI-A mRNAs,
respectively.
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Fig. 4.
Film autoradiography showing expression of
c-fos mRNA in response to IMO stress
with or without pretreatment with various drugs. Con, control; TNG,
nitroglycerin; Dil, diltiazem; Lido, lidocaine; Pra, prazosin; Met,
metoprolol; Amo, amosulalol. Note that pretreatment with TNG, Dil,
Lido, Pra, or Met could not suppress upregulation of
c-fos mRNA, whereas pretreatment with
a combination of Pra and Met or with Amo could completely abolish
stress-induced expression of c-fos
mRNA.
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Fig. 5.
Semiquantitative analysis of c-fos
(A) and NGFI-A (B) mRNA
levels in response to IMO stress with or without pretreatment with
various drugs. Data are means ± SD normalized to values for
untreated control group. ** P < 0.01 compared with Pra + Met + IMO or Amo + IMO.
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Treatment of the perfused heart with the
1-agonist phenylephrine or the
-agonist isoproterenol, or the combination thereof, elicited a
strong expression of c-fos and NGFI-A
mRNAs, moderate or weak expression of
fos B,
c-jun,
jun B, and NGFI-B mRNAs, and very weak
expression of jun D mRNAs (Fig.
6). The strongest mRNA signals were observed in the
endothelial cells (Fig. 3). The moderate signals were found in the
myocardial cells in response to both IMO stress and stimulation with
- and/or -agonists (Fig. 3). Semiquantitative analysis of these
mRNA levels is shown in Fig. 7. Relative
mRNA levels for c-fos increased
significantly after treatment with
1- and -agonists, singly or
combined, or after immobilization for 30 min. Similarly, relative mRNA
levels for fos B,
c-jun,
jun B, and NGFI-A were also
significantly upregulated in response to these drugs or IMO. There were
no significant differences in relative mRNA levels for
c-fos or NGFI-A among
1- and -agonists, singly or
combined, or after immobilization. Relative mRNA levels for NGFI-B were
significantly higher only in the groups pretreated with - and
-agonists combined or IMO stress. No significant changes occurred in
jun D mRNA levels in any of the
groups.
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Fig. 6.
Film autoradiography showing expression of
c-fos mRNA in heart perfused with
buffer alone (Con) or with buffer containing phenylephrine (Alpha),
isoproterenol (Beta), or phenylephrine plus isoproterenol (Alpha/Beta).
Note that stimulation by both - and -agonists induced
c-fos,
fos B,
c-jun,
jun B, NGFI-A, and NGFI-B mRNAs.
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Fig. 7.
Semiquantitative analysis of c-fos
(A),
fos B
(B),
c-jun
(C),
jun B
(D),
jun D
(E), NGFI-A
(F), and NGFI-B
(G) mRNA levels in response to
stimulation by 1- and/or
-agonists or IMO stress for 30 min. Data are means ± SD
normalized to values for untreated control group (Con).
* P < 0.05;
** P < 0.01 compared with Con.
#1 P < 0.05, 1/-agonist vs. IMO
group;
#2 P < 0.05, -agonist vs. IMO group;
#3 P < 0.05, 1/-agonist vs. IMO
group. NS, not significant.
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| |
DISCUSSION |
Using in situ hybridization histochemistry, we studied the molecular
changes that follow IMO stress in discrete types of cardiac cells. A
rapid and transient upregulation of IEG mRNAs, including c-fos, NGFI-A,
c-jun,
fos B,
jun B, and NGFI-B mRNAs, was observed in the endothelial cells, in myocardial cells of the left and right
ventricles (particularly in the endocardial side), and in smooth muscle
cells of the coronary arteries. Because the induction of IEGs indicates
cellular activation, these results suggest that this type of stress
activates individual types of cells, and some of these effects show a
unique regional pattern.
The second important finding of this study is that activation of either
- or -adrenoceptors is essential in the induction of IEGs.
Pretreatment with an
1-adrenoceptor blocker, a
1-adrenoceptor blocker, a
calcium-channel blocker, a class Ib antiarrhythmic drug, or
nitroglycerin did not suppress the upregulation of IEGs. In these
experiments, because we did not monitor the precise hemodynamic changes
such as blood pressure, cardiac output, or coronary blood flow, we
cannot rule out the contribution of hemodynamic changes in inducing
gene expression. However, the drug doses chosen were calculated to
prevent a rise in blood pressure (3, 11, 13, 17) or to protect against
ischemia-induced arrhythmia (2), making it unlikely that
hemodynamic factors were involved in the findings. The failure of the
potent coronary vasodilators such as the calcium-channel blocker or
nitroglycerin to inhibit IEG expression suggests that ischemia
and/or reperfusion were probably not responsible for IEG upregulation
evoked by IMO stress. In the neurons, the influx of extracellular
calcium or sodium ions activates these cells, thereby inducing IEGs
(40). These pathways also were not involved in the activation of IEGs
in the heart in response to emotional stress, because L-type
calcium-channel blocking by diltiazem and sodium-channel blocking by
lidocaine were ineffective.
On the other hand, the combined blockade of
1- and
1-adrenoceptors by pretreatment
with prazosin plus metoprolol or with amosulalol, respectively,
completely abolished the stress-induced gene expression of all the
IEGs. This result indicates that the inhibition of both
1- and
1-adrenoceptors is essential to
prevent IEG expression in cardiac cells from being evoked by IMO
stress. As shown in Figs. 3 and 7, the intensities and distribution of signals among the cells of the heart perfused with adrenergic agonists
under constant pressure and enough oxygenation were indistinguishable from those in heart cells from rats experiencing IMO stress. This second line of data indicates that the activation of either - or
-adrenoceptors is sufficient to mimic the response evoked by IMO
stress in the rat and to exclude the possibility that mechanical stretch (pressure overload) and ischemia-reperfusion are
involved in the IEG induction. These results seem to be coincident with the distribution of adrenoceptors in the rat heart (8). In the human
heart, 1-adrenoceptor is
predominant and the density of
1-adrenoceptor is very low
(42), whereas, in the rat heart, the densities of
1- and
1-adrenoceptors are almost
equal (19, 26). It is reported that psychosocial stress or
pharmacological activation of the sympathetic nervous system induces
endothelial injury, which can be prevented by
1-blockers in both monkeys (36)
and rabbits (29). Endothelial functions are also mediated directly by
1-adrenoceptor (38). These
reports suggest the presence of - and -adrenoceptors on
endothelial cells.
Finally, our data also suggest that both - and
-adrenoceptor-mediated signal transduction pathways may converge or
cross talk with each other, resulting in the transcription of mRNAs for
these IEGs. Selective activation of - or -adrenoceptor induced similar patterns of gene expression in cardiac cells because both the
cAMP-mediated pathway and the protein kinase C-mediated pathway are
closely involved in the transcription of
c-fos (20). However, activation of
both receptors did not show any significant additive augmentation of
expression except for NGFI-B mRNA levels (Fig. 7). The cross talk
between - and -adrenoceptors in cardiomyocytes and cardiac
muscles has also been suggested in other studies. For example, the
inotropic response of isolated papillary muscles by - and
-adrenoceptor stimulation showed a mutual inhibition of one
component on other (37). The activation of
1-receptor stimulated cAMP
phosphodiesterase activity, thereby decreasing -adrenergic-mediated
cAMP levels in isolated cardiomyocytes (5). Reciprocally,
-adrenoceptor- and forskolin-induced cAMP production had an
inhibitory effect on
1-adrenoceptor-mediated
inositol phosphate response (9). The overexpression of
1B-adrenoceptor negatively
modulated -adrenoceptor signaling in the heart of transgenic mice
(18). However, the precise mechanisms of cross talk between - and
-adrenoceptors in discrete cardiac cells are still unknown.
In conclusion, IMO stress induced the upregulation of IEGs in
endothelial cells, myocardial cells, and smooth muscle cells of the
coronary arteries. The activation of - or -adrenoceptors is the
primary trigger of emotional stress-induced expression of IEGs in these
discrete cardiac cells. Cross talk of signal transduction downstream
from - and -adrenoceptors in these cardiac cells is also suggested.
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ACKNOWLEDGEMENTS |
We are grateful to Profs. Edith D. Hendley (Department of Molecular
Physiology and Biophysics, University of Vermont, Burlington, VT) and
Arthur D. Loewy (Department of Anatomy and Neurobiology, Washington
University School of Medicine, St. Louis, MO) for helpful comments and
careful reading of the manuscript.
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FOOTNOTES |
This work was supported by a grant from the Japan Foundation of
Cardiovascular Research (Tokyo, Japan) (to T. Ueyama), a Young Investigator's Award (Wakayama Prefectural Government, Wakayama, Japan) (to T. Ueyama), and Grants-in Aid for Scientific Research from
the Ministry of Education, Science and Culture of Japan (09670740) (to
T. Ueyama).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Ueyama, Dept.
of Anatomy, Wakayama Medical College, Wakayama 641-8509, Japan (E-mail:
tueyama{at}wakayama-med.ac.jp).
Received 23 September 1998; accepted in final form 19 May 1999.
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Am J Physiol Heart Circ Physiol 277(4):H1553-H1561
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