CARDIOVASCULAR JOURNAL OF AFRICA • Vol 22, No 6, November/December 2011
AFRICA
313
Role of stromal-derived factor-1<alpha>/CXCR4 in
neo-intimal repair
J SHENG, W-W CAI, N-Y FANG, S-Q WANG, J-J WU
Abstract
Neo-intimal hyperplasia is one of the major causes of reste-
nosis in which stromal cell-derived factor-1<alpha> (SDF-1
a
)
and its receptor CXCR4 play an important role. In a rat
common carotid artery balloon injury model, the number of
CD34
+
CXCR4
+
cells was significantly increased immediately
after injury (
p
<
0.01), followed by a gradual decrease to
baseline seven days after the injury. Furthermore, the plasma
(SDF-1
a
) level was markedly elevated, and peaked 24 hours
after injury (
p
<
0.01), followed by a rapid decrease to base-
line level seven days after the injury. In the injured common
carotid artery, the mRNA expression of (SDF-1
a
) was elevat-
ed immediately after injury, followed by a gradual decline,
but that of CXCR4 was increased four days after injury.
Immuno-histochemistry displayed CXCR4-positive stain-
ing one day after injury, which then gradually increased and
continued for at least one month. In addition, administration
of AMD3100 (200 ng/kg, i.p.), a CXCR4 antagonist, did not
affect the number of CD34
+
CXCR4
+
cells, the elevated level
of plasma (SDF-1
a
) and expression of (SDF-1
a
) mRNA.
The expression of CXCR4 mRNA and protein however was
markedly decreased, and detectable CXCR4-positive cells
occurred four days after injury, followed by a decreased
intensity of staining. We also found that, three months after
balloon injury, stenosis of the carotid artery intima in the
group that received AMD3100 was significantly less than in
the untreated group (
p
<
0.05). Therefore, (SDF-1
a
)/CXCR4
played a crucial role in the intimal hyperplasia, and resteno-
sis may have be attenuated after inhibition of CD34
+
CXCR4
+
cells in the intima.
Keywords:
percutaneous transluminal coronary angioplasty,
percutaneous coronary intervention, restenosis, chemokine,
stromal cell-derived factor-1<alpha>, CXCR4
Submitted 30/11/09, accepted 31/8/10
Cardiovasc J Afr
2011;
22
: 313–318
DOI: 10.5830/CVJA-2010-075
Percutaneous transluminal coronary angioplasty (PTCA) and
percutaneous coronary intervention (PCI) are effective tech-
niques in the treatment of cardiovascular diseases, including
acute myocardial infarction (AMI). But a relatively high inci-
dence of restenosis after PTCA or PCI is a major problem, caus-
ing failure of treatment. Neo-intimal hyperplasia after vascular
injury plays an important role in post-treatment restenosis, which
is mainly caused by excessive cell deposition in the neo-intima.
Therefore, blocking cell deposition may be a promising strategy
in the prevention of post-injury restenosis.
Stromal cell-derived factor-1 (SDF-1) is one of the chemokines
that belong to the intercrine family and is officially designated
as chemokine (C-X-C motif) ligand 12 (CXCL12).
1
The recep-
tor for this chemokine is CXCR4, which was previously called
fusin. SDF-1 is a strong chemo-attractant in directing progenitor
cell trafficking, cell migration and angiogenesis.
2,3
It has been
confirmed that the expression of SDF-1 was elevated in the
peri-infarct area after AMI,
4
which recruited CXCR4
+
cells to
participate in myocardial repair and angiogenesis.
In humans and rats, both SDF-1 and CXCR4 show a high
degree of sequence homology. In rats, the SDF-1 gene encodes
three splice variants:
α
,
β
and
γ
. In the present study, a rat
carotid artery balloon injury model was used to mimic human
coronary neo-intimal repair after PTCA or PCI. By investigating
the expression of SDF-1
α
and CXCR4 after injury and using a
CXCR4 antagonist (AMD3100) to block the interaction between
SDF-1 and CXCR4, we found that SDF-1
α
/CXCR4 played a
critical role in neo-intimal hyperplasia.
Methods
A total of 156 male Sprague Dawley rats weighing 286
±
14.3 g
were purchased from the SLAC Laboratory Animal Co, Ltd,
Shanghai, China, and housed in a temperature-controlled envi-
ronment (22–24°C) with a 12-h light–dark cycle. The local
ethics committee of the School of Medicine, Shanghai Jiao-Tong
University (No. 0708253) approved all procedures.
The rats were randomly divided into three groups: a control
group (group C;
n
=
12), a surgical group (group S;
n
=
72), and
the AMD3100 treatment group (group A,
n
=
72). The rats in
groups S and A were further divided into six sub-groups (
n
=
12
per group).
The rats were sacrificed as follows. Groups S
0
and A
0
were
sacrificed 30 min after surgery, groups S
1d
and A
1d
one day after
surgery, groups S
4d
and A
4d
four days post surgery, groups S
7d
and
A
7d
seven days after surgery, groups S
1m
and A
1m
one month after
surgery, and groups S
3m
and A
3m
three months post surgery.
The rat common carotid artery balloon injury model was
carried out in groups S and A as previously described,
5
and rats
in the control group underwent a sham operation. Briefly, the
rats were intraperitoneally anaesthetised with 2.5% pentobarbital
sodium (40 mg/kg) and fixed in the supine position. A midline
incision was made in the neck, and then the left common carotid
Department of Geriatrics, 9th Hospital, Shanghai Jiao-Tong
University School of Medicine, Shanghai, China
J SHENG, MD
W-W CAI,
S-Q WANG,
Department of Geriatrics, Ren-Ji Hospital, Shanghai Jiao-
Tong University School of Medicine, Shanghai, China
N-Y FANG, MD
Shanghai Tissue Engineering Laboratory, Shanghai Jiao-
Tong University School of Medicine, Shanghai, China
J-J WU
