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Distribution of ╬║-Opioid Receptor in the Pulmonary Artery and its Changes During Hypoxia.

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THE ANATOMICAL RECORD 292:1062–1067 (2009)
Distribution of j-Opioid Receptor in the
Pulmonary Artery and its Changes
During Hypoxia
PAI PENG,1,2 LU-YU HUANG,3 JUAN LI,2 RONG FAN,2 SHU-MIAO ZHANG,2
YUE-MIN WANG,2 YU-ZHEN HU,2 XIN SUN,2
ALAN DAVID KAYE,4,5 AND JIAN-MING PEI2*
1
Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University,
Xi’an, China
2
Department of Physiology, National Key Discipline of Cell Biology,
Fourth Military Medical University, Xi’an, China
3
Department of Orthopaedics, Xijing Hospital,
Fourth Military Medical University, Xi’an, China
4
Department of Anesthesiology, LSU School of Medicine, New Orleans, USA
5
Department of Pharmacology, LSU School of Medicine, New Orleans, USA
ABSTRACT
The present study evaluated the distribution of j-opioid receptors
(j-ORs) in pulmonary arteries (PAs) in rats and investigated whether
j-ORs are altered in PAs during hypoxia. An animal model of hypobaric/
hypoxic pulmonary hypertension and a pulmonary artery smooth muscle
cell (PASMC) model of hypoxia were utilized. Distribution of j-ORs was
determined by fluorescence immunohistochemistry and changes in j-ORs
expression in PAs and PASMCs were determined by fluorescence immunohistochemistry or Western blot techniques. The j-ORs were primarily
distributed in the smooth muscle layer of the PAs and in the nucleus of
PASMCs. The expression of the j-ORs were increased in PAs of rats subjected to hypoxia for 1–4 week (P < 0.01). Accordingly, the expression of
j-ORs in PASMCs were also increased when subjected to hypoxia for 12–
36 hr (P < 0.05). The present study has provided evidence for the first
time of the precise location of j-ORs in PAs and PASMCs of rats and
that hypoxia upregulates expression of j-ORs. Anat Rec, 292:1062–1067,
C 2009 Wiley-Liss, Inc.
2009. V
Key words: j-opioid receptor; pulmonary artery; hypoxia
The j-opioid receptor (j-OR) is a class of opioid receptor first described by Martin (1983). j-ORs have been
identified in the brain, the spinal cord, and the periphery (Gray et al., 2005), including the vascular system.
Radioimmunology competitive binding assays and functional studies have demonstrated that the j-ORs are the
predominant type of opioid receptors, which exist in peripheral vessels (Tai et al., 1991; Wittert et al., 1996).
Seelhorst and Starke (1986) showed that it was likely
that receptors in the pulmonary artery of the rabbits are
at least, predominantly kappa-type. Our previous study
demonstrated for the first time that a selective j-opioid
receptor agonist, U50,488H, relaxed pulmonary arteries
C 2009 WILEY-LISS, INC.
V
Grant sponsor: Department of Health, General Department of
Logistic, PLA; Grant number: 01MB129, 06MA203; Grant
sponsor: National Natural Science Foundation, China; Grant
number: 30770802.
*Correspondence to: Jian-Ming Pei, Department of Physiology, Fourth Military Medical University, Changle west Road
17#, Xi’an, Shaan Xi, China. Fax: 86-029-84774519.
E-mail: jmpei8@fmmu.edu.cn
The first three authors contributed equally to this work.
Received 18 November 2008; Accepted 27 February 2009
DOI 10.1002/ar.20911
Published online 21 May 2009 in Wiley InterScience (www.
interscience.wiley.com).
j-OR IN PULMONARY ARTERY
in vitro, and decreased pulmonary pressure in vivo in
rats (Pei et al., 2006; Sun et al., 2006), indicating that jORs may exist in pulmonary arteries (PAs) in rats. However, the exact distribution of j-ORs in PAs and how
they change during hypoxia still remains largely uncertain. In the present study, our first aim was to investigate the distribution of j-ORs in the pulmonary artery
and its changes under hypoxic conditions in rats. This
objective was approached by western-blot and fluorescence immunohistochemistry. Then, we tested these
results in primary cultured pulmonary artery smooth
muscle cells (PASMCs). The present study revealed a
definite location of j-ORs in the PASMCs, which is different in cardiomyocytes. In addition, the expression of
the j-ORs was altered during hypoxic conditions.
MATERIALS AND METHODS
Animal Groups and Rat HPH Model
Thirty-two male Sprague-Dawley rats (250 20 g)
from the animal center of the Fourth Military Medical
University (This study conformed to the Guide for the
Care and Use of Laboratory Animals published by the
U.S. National Institutes of Health) were divided into 4
groups: (1) normoxic group, normal control group; (2) hypoxia for 1-week group, the rats were exposed to hypobaric and hypoxic conditions for 1 week; (3) hypoxia for
2-week group, the rats were exposed to hypobaric and
hypoxic conditions for 2 weeks; (4) hypoxia for 4-week
group, the rats were exposed to hypobaric and hypoxic
conditions for 4 weeks.
The animal model of hypobaric and hypoxic pulmonary
hypertension was performed with automatic hypoxia
equipment (Pei et al., 2006). Hypoxia was performed for
8 hr every day by exposing rats to low pressure and low
oxygen (air pressure 50 kpa, oxygen concentration 10%).
The normoxic group of rats was kept in room air.
Tissue Treatment
After hypoxia, rats were anesthetized with peritoneal
injection with 30 g L1 pentobarbital sodium (1.5 mL
kg1, ip). The skin was sterilized with 75% alcohol, then
the chest was opened, and the heart and lungs were
removed. The organs were placed into PBS (pH 7.4,
4 C); The studied tissues were extracted from the same
position of the inferior lobe of the right lung, and fixed
in 10% formalin (pH 7.4) for 1 week.
PA were gently isolated and not stretched during the
preparation. A three grade branch of PA were picked,
fixed in 4% paraform solution for 48 hr, and then the artery were removed and un-hydrated in sucrose solution
step by step (10%, 20%, 30%), then 6-lm frozen sections
were prepared, and tissue slices were stored at 80 C.
The rest of the tissues were held in liquid nitrogen for
10 min and then were stored at 80 C.
1063
right ventricular pressure (RVP) were measured. Right
ventricle (RV), left ventricle (LV), and septum (S) were
isolated, and after the absorbing of water using filter paper, RV and LVþS was weighed. The RV/(LVþS) and RV/
BW (body weight) ratios were calculated and used as
indexes for right ventricular hypertrophy.
Fluorescence Immunohistochemistry
The frozen sections were taken out from the refrigerator (80 C), placed in room temperature for 30 min, and
then they were soaked in 1% PBS for 5 min and endogenous peroxidase were inactivated with 3% H2O2 (diluted
with methanol) for 30 min. After washed with 1% PBS,
the sections were blocked with 10% goat blood
serumþ5% bovine albumin for 20 min, then the sections
were incubated overnight with rabbit polyclonal IgG [jOR-1 (H-70), Santa Cruz Biotechnology] at 4 C, after
surplus IgG[j-OR-1 (H-70)] was washed off, the samples
were incubated with a second rabbit IgG(HþL)/TRITC
for 45 min at 37 C, surplus anti-rabbit IgG (HþL)/
TRITC were washed off, the sections were blocked with
50% glycerol, and PAs were imaged with an Olympus
fluorescent microscope (400). Ten fields of view were
selected in every sample randomly (400); positive cells
were counted with image pro-plus software.
Determination the Expression of j-ORs by
Western-Blot
The PAs were minced and homogenized in lysis buffer
(Tris 20 mM, NaCl 50 mM, NaF 50 mM, Na4P2O710H2O
5 mM, C12H22O11 25 mM, DTT 1 mM, Na3VO4 2 mM
and 1% protease inhibitor cocktail, pH 7.4) by a Heidolph DIA900 tissue homogenizer (Heidolph Instruments
GmbH, KG, Schwabach, Germany) (Li et al., 2007). The
homogenate was centrifuged (12,000g at 4 C for 10 min),
the supernatant was decanted, and total protein level
was determined with a BSA assay kit.
After the aforementioned protocol, equal amounts of
protein was electrophoresed in SDS-polyacrylamide gel,
and electrophoretically transferred to a poly (vinylidene
difluoride) membrane (Millipore, Billerica, MA). After
blocking with 5% skim milk in TBS at room temperature
for 1 hr, the membrane was incubated with a rabbit polyclonal IgG[jOR-1 (H-70)] overnight at 4 C. The membrane was then washed with PBS and incubated with a
HRP-conjugated IgG antibody for 1 hr at 37 C. b-actin
was selected as a housekeeping protein and was analyzed following the same procedure, using a specific antib-actin mouse monoclonal antibody.
The straps were developed with an enhanced chemiluminescence detection kit (Pierce Biotechnology, Rockford,
IL). Immunoblotting was visualized with ChemiDocXRS
(Bio-Rad Laboratory, Hercules, CA), and the relative
value of the protein densities were analyzed with Lab
Image software.
Hemodynamics in Hypoxia
After hypoxia for 30 min, rats were anesthetized with
peritoneal injection with 30 g L1 pentobarbital sodium
(1.5 mL kg1, ip). According to Michelakis et al. (2002),
a microcatheter was inserted into right ventricle and
pulmonary artery through right external jugular vein,
and the mean pulmonary arterial pressure (mPAP) and
Primary PASMCs Culture and
Immunohistochemistry Staining of Actin
Sprague–Dawley male rats (180–200 g) were anesthetized with a peritoneal injection of 30 g L1 pentobarbital sodium (1.5 mL kg1, ip) and skin was sterilized with
75% alcohol. Chest was opened, and heart and lung
1064
PENG ET AL.
TABLE 1. Changes in hemodynamics in rats exposed to chronic hypoxia
Group
Control
1-Week hypoxia
2-Week hypoxia
4-Week hypoxia
mPAP (mmHg)
15.2
25.5
27.9
32
2.3
1.8a
2.2a
3.3a
RVP (mmHg)
25.6
34.8
35.6
36.8
1.7
2.1a
1.7a
2.0a
RV/(LVþS)
0.26
0.30
0.38
0.41
0.04
0.04
0.06a,b
0.07a,b,c
RV/BW (mg/g)
0.58
0.65
0.90
0.99
0.06
0.07
0.06a,b
0.08a,b,c
N ¼ 8; 1 mmHg ¼ 0.133 kPa.
mPAP, mean pulmonary artery pressure; RVP, right ventricular pressure; RV, right ventricle;
LV, left ventricle; S, septum; BW, body weight.
a
P < 0.01 versus control.
b
P < 0.01 versus 1-week hypoxia group.
c
P< 0.01 versus 2-week hypoxia group.
were removed. The organs were placed into D-hanks solution (Ca2þ and My2þ-free, pH 7.4, 4 C) and rinsed for
several times. The PAs were segregated in a sterile manner, and then the obtained PASMCs were cultured as
previously described (Campbell et al., 1979). Briefly, the
outer spheres were peeled and the microtubules were
sniped visually, endotheliums were shaved slightly for
2–3 times to remove endothelial cells. The tunica medias
were placed in a DMEM culture solution, then prepared
into scraps (1 mm3) where these primary PASMCs were
cultured (37 C, 5%CO2; the culture solution was DMEM
containing 20% fetal bovine serum). PASMCs were found
to be surrounding the scraps of the PA about 4–7 days
later. The third to sixth generations of cells were used
for the experiments.
The PASMCs were seeded onto glass coverslips, then
they were fixed in pure liquor pyroaceticus for 20 min,
washed with distilled water, and the endogenous peroxydase was inactivated by 0.5%H2O2 (diluted with methanol) for 30 min. After washed with distilled water, the
PASMCs were blocked with 10% goat blood serum for 20
min at room temperature, and then incubated overnight
with rabbit polyclonal a-actin (Sigma Company) at 4 C.
After washed off with 1%PBS, the samples were incubated with 1% anti-rabbit IgG for 20 min at 37 C, then
the surplus anti-rabbit IgG were washed off with 1%
PBS, and then the samples were incubated with 1%
SABC for 20 min at 37 C. After been washed, the samples were stained with DAB and hematoxylin, cells were
imaged with a light microscope.
Light microscopic observation of cultured rat PASMCs,
PASMCs crept from tissue pieces like Fusiform shape,
After 4–7 days, they demonstrate typical morphological
patterns (multilayer sheets and ‘‘hills and valleys’’).
Immunohistochemistry staining of actin in rat PASMC
showed that a-actin distributed in cytoplasm in yellow.
Cells were divided into 5 groups: (1) normal oxygen
state, (2) hypoxia for 12 hr, (3) hypoxia for 24 hr, (4) hypoxia for 36 hr, (5) hypoxia for 48 hr. Hypoxic groups
were cultured in an incubator (37 C, 2%O2, 5% CO2,
93%N2) (Kendro, Germany). The hypoxia exposures were
initiated at different times according to the durance of
the hypoxia exposure so the hypoxia exposures were
ended at the same time. After hypoxia, experiments for
all the five groups were performed at the same time.
Cell Fluorescence Immunohistochemistry
The PASMCs were seeded onto glass coverslips, fixed
in 4% paraform solution for 20 min, then washed in 1%
PBS for 5 min 3 times, and inactivated by endogenous
peroxidase with 3%H2O2 (diluted with methanol) for 30
min. After washed in 1% PBS for 5 min 3 times, the
samples were blocked with 10% goat blood serum and
5% bovine albumin for 20 min, then incubated overnight
with rabbit polyclonal IgG [jOR-1 (H-70)] at 4 C. After
surplus rabbit IgG [jOR-1 (H-70)] were washed off, the
samples were incubated with anti-rabbit IgG (HþL)/
TRITC for 45 min at 37 C, then the surplus anti-rabbit
IgG (HþL)/TRITC was washed off, and finally the samples were incubated with Hoechst 33258 for 5 min, and
rinsed for 5 min 3 times. Cover slips were blocked
with 50% glycerol and cells were imaged with the Olympus fluorescent microscope (400). The value of the protein densities were analyzed with image pro-plus
software (Media Cybernetics). Mean fluorescence intensity of TRITC was measured by a gray scale value
(Changez et al., 2006). Ten fields of view in each sample
were selected at random (400) to measure cell fluorescence intensity with image pro-plus software.
Antibody and Kit
Rabbit polyclonal IgG [jOR-1 (H-70)] (sc-9112) (j-OR-1
is a rabbit polyclonal antibody raised against amino
acids 1–70 of j-OR-1 of human origin, and its molecular
weight is 58 kDa), and Actin primary antibody (sc1616r) were purchased from Santa Cruz Biotechnology.
The secondary antibody (goat anti-rabbit antibody) conjugated with HRP was purchased from Boshide company. Rabbit IgG (HþL)/TRITC made by Dingguo
Company in Beijing. Protein Quantitation Kit and chemiluminescence kits were purchased from Pierce
Company.
Statistical Analysis
Values are presented as mean SD. One-way ANOVA
was employed to determine the difference among groups.
Significance level was set at P < 0.05.
RESULTS
Hemodynamics in Hypoxia
Pulmonary hypertension developed after 1 week of hypoxia in the rats. Compared with the normal oxygen state
control group, the mPAP (Gong et al., 2004), the RVP, the
RV/ (LVþS) ratio and the RV/BW ratio of the hypoxia state
group all increased significantly in all three hypoxic
groups. Aforementioned changes were typical at 2 weeks
and more significant at 4 weeks (Table 1).
j-OR IN PULMONARY ARTERY
1065
Fig. 2. Changes of expression of j-ORs protein in hypoxia (N ¼ 6).
P < 0.01 vs. control group; bP < 0.01 versus hypoxia for 2-week
group. (Molecular weight of j-OR-1: 58 kDa).
a
Fig. 1. Expression of j-opioid receptors in PAs (400, N ¼ 6).
Expression of j-opioid receptors in inner membrane (*), in outer membrane (#), and mainly in the layer of SMC (arrows) in PAs. Panel a: A,
Negative; B, 10% goat blood serum replaced IgG [jOR-1 (H-70)]; C,
normaxic group; D, Hypoxia for 1 week group; E, Hypoxia for 2-week
group; F, Hypoxia for 4-week group. Panel b: Group results, aP < 0.01
versus control group, bP < 0.01 versus hypoxia for 2 week group.
Expression of j-ORs in PAs During Hypoxia
The j-OR was distributed in all three layers of the
PAs. Results of fluorescence immunohistochemistry
(Fig. 1) demonstrated that j-ORs were mainly distributed in the layer of the smooth muscle.
Results of fluorescence immunohistochemistry (Fig. 1b)
and Western-Blot (Fig. 2) demonstrated that expression of
the j-OR increased significantly in the PA during hypoxia (P
< 0.01). Expression of the j-ORs reached maximum after 2
week of hypoxia (P < 0.01). The j-ORs expression returned
to the 1 week level after prolonged hypoxia for 4 week.
Expression of j-ORs in PASMCs
During Hypoxia
The j-ORs were located in the nucleus of normal
PASMCs, appearing as a relatively large particle, while
the expression of the j-ORs increased during hypoxia (P
< 0.05, N ¼ 10). Expression of the j-ORs reached maximum after 24 hr of hypoxia (P < 0.01). Additionally, the
morphology of the j-ORs appeared as a relatively small
particle under hypoxic conditions (Fig. 3a,b). We used
the same method in primary cultured cardiomyocytes
and found that j-ORs are located in plasma membrane
and cytoplasm in cardiomyocytes (Fig. 3aI).
DISCUSSION
The major findings in the present study are: (1) j-ORs
were mainly distributed in the smooth muscle layer of
the PAs; (2) j-ORs were mainly located in the nucleus in
the normal PASMCs, appearing as a relatively large particle, and the morphology of the j-ORs was altered into
a relatively small particle under hypoxia conditions; (3)
expression of the j-ORs in the PAs and the PASMCs
were significantly increased during hypoxia.
Our previous studies (Pei et al., 2006; Sun et al.,
2006) showed that j-ORs might be located in the PAs of
the rat. The present study has demonstrated that j-ORs
are located in the PAs of the rat. Further, the j-ORs
were mainly distributed in the smooth muscle layer of
the PAs, and correspondingly, the j-ORs were mainly
located in the nucleus of the normal PASMCs.
It is well known that opioid receptors belong to a
super family of G-protein coupled receptors, which are
characterized by seven transmembrane hydrophobic
regions and it has been reported that the j-ORs exist in
cardiac tissue (Ventura et al., 1989; Tai et al., 1991; Jin
et al., 1995; Peart et al., 2008). Consistent with these
studies, we utilized the same method in the primary cultured myocardial cell and found that j-ORs were located
in the plasma membrane and the cytoplasm in myocardial cells. Svingos and Colago et al. (2002) have reported
that j-ORs are localized in intracellular compartments
and plasma membranes of individual dendrites. OP4
(ORL1, NOP1) receptors particularly concentrate in the
perinuclear area with a granular pattern in endothelial
cells from various vascular regions (Granata et al.,
2003). The construction of OP4 receptors is similar to
that of j-ORs. Therefore, we hypothesize that the distribution of the j-OR may be dissimilar in different types
of cells.
Our previous studies (Liu et al., 2008) have showed
that the expression of j-ORs upregulated in the heart of
I/R (ischemia and reperfusion) rats. Bhargava et al.
(1997) showed that j-opioid receptors density was
1066
PENG ET AL.
Fig. 3. Expression of j-ORs in PASMCs and cardiomyocytes with
fluorescence immunohistochemistry (400, N ¼ 10). Panel a: A, Negative; B, Control; C, Hypoxia for 24 h; D, Hypoxia for 12 h; E, Hypoxia
for 12 hr (Hoechst 33258); F, Hypoxia for 12 hr (merge D and E);
G, Hypoxia for 48 hr; H, nucleus (incubated with Hoechst 33258) of
PASMCs with the same view of E; I, cardiomyocytes. Arrows showing
the j-ORs (red) in PASMCs and cardiomyocytes, nucleus (blue) incubated with Hoechst 33258. To testify that our method for determination of j-ORs distribution in PASMCs is correct, we used the same
method in primary cultured cardiomyocytes and found that j-ORs
locate in plasma membrane and cytoplasm in cardiomyocytes (I).
Panel b: Group results of IOD (OD/lm2),cP < 0.05, aP < 0.01 versus
control group, bP < 0.05 versus hypoxia for 12 hr, dP < 0.01 versus
hypoxia for 24 hr.
augmented in sensitized lung parenchyma, while l- and
d-opioid receptor densities were decreased in sensitized
main bronchus and lung parenchyma, respectively, compared to normal tissues. In the present study, we found
that expression of j-ORs in the SMC layer of PAs were
increased during hypoxia. In order to further determine
changes of j-ORs expression in hypoxia, we cultured primary PASMC and found that the expression of j-ORs
was increased in hypoxia. The results are consistent
with the above mentioned results in vivo. Qing, et al.
(2001) reported an upregulation of CGRP and ADM
receptors in the lung of rats exposed to 1 and 2 week of
chronic hypobaric hypoxia. Other investigators have
shown that ETA receptors are increased in the lungs of
chronically hypoxic rats (Li et al., 1994; Soma et al.,
1999). These studies indicate that receptors of vasomotor
factors may significantly increase in hypoxia. But the
underlying mechanisms are still unknown. Numerous
laboratories have shown that the plasma level of Dynorphin A, an endogenous j-OR agonist, has been shown to
increase significantly after hypoxia (Lu et al., 1997;
Shen et al., 1998). And our previous research revealed
that Dynorphin A can relax the PA (Sun et al., 2006)
and also showed that U50,488H, a selective j-OR agonist, decreased mean mPAP in vivo in rats. Thus, it is
possible that an increased level of Dynorphin stimulates
the expression of j-ORs during hypoxia. Further, the
lasting release of endogenous Dynorphin down regulates
the expression of j-ORs in the PAs after hypoxia for 2
week. It should be noted that the mPAP, the RVP, the
RV/ (LVþS) ratio and the RV/BW ratio of hypoxia groups
were all increased significantly compared with the normal oxygen control group. These changes were typical at
2 weeks and more significant at 4 weeks. Lachmanová
et al. (2005) showed that free radical injury can happen
in the pulmonary vascular wall in early under hypoxic
exposure. We hypothesize that the injury induced by hypoxia may also impact the expression of j-ORs after hypoxia for 2 week. But the underlying mechanism of the
increasing expression of the j-ORs during hypoxia needs
further investigation. In the future, we hope to elucidate
whether the release of endogenous Dynorphin changes
during hypoxia, and/or whether nor-binaltorphimine, a
selective j-opioid receptor antagonist, inhibits the
expression of j-ORs in the PAs of the rat exposed to hypoxia for 2 week compared with normal oxygen control
group.
In conclusion, the present study has provided evidence
for the first time of the precise location of the j-ORs in
the PAs and PASMCs in rats, and that hypoxia induces
an increased expression of j-ORs in the PAs. These findings along with our previous studies (Sun et al., 2006;
Pei et al., 2006) support a functional role for j-ORs in
regulating the pulmonary circulation. Further, the
results of the present study suggest that j-ORs might be
a potential treatment target in the clinical setting of
hypoxic-induced pulmonary disease states.
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