Circulation Journal

Official Journal of the Japanese Circulation Society

REVIEW
http://www. j-circ.or.jp

Role of the SDF-1/CXCR4 System in Myocardial Infarction

Masafumi Takahashi, MD

Myocardial infarction (MI) is accompanied by an inflammatory response, leading to the recruitment of leukocytes
and subsequent myocardial injury and healing. Chemokines are potent chemoattractant cytokines that regulate
leukocyte trafficking in inflammatory processes. Recent evidence indicates that chemokines play a role not only
in leukocyte trafficking but also in angiogenesis and cardioprotection. In particular, stromal cell-derived factor-1α
(SDF-1α) has generated considerable interest for its role in the pathophysiology of MI. This review will focus
on the role of SDF-1 and its receptor CXC chemokine receptor 4 (CXCR4; ie, the SDF-1/CXCR4 system) in the
pathophysiology of MI and discuss their potential as therapeutic targets for MI.   (Circ J  2010; 74: 418 – 423)

Key Words: Cardioprotection; Chemokines; Endothelial progenitor cells; Leukocytes; Myocardial infarction

I
schemic heart disease is a common occurrence, and in
the near future it is predicted to be the leading cause of
death worldwide. Myocardial infarction (MI) is a com-
mon presentation of ischemic heart disease and is defined as
interruption of the blood flow to the heart because of the
occlusion of a coronary artery and the replacement of necrotic
myocardium by a dense fibrotic scar. The main functional
consequence of MI is a decrease in systolic compliance (ie,
progressive loss of pump function in the chamber where the
muscle has been lost). In addition, MI often results in elec-
trical instability within the heart and the generation of fatal
arrhythmias. Therefore, the development of ischemic heart
disease, including MI, is an important issue requiring study.
Despite the advancement in revascularization procedures
for ischemic heart disease, including MI, a substantial num-
ber of patients are either not eligible for these procedures
or only partial revascularization can be achieved for them.
Inducing angiogenesis by the administration of exogenous
angiogenic factors or the transfer of genes coding for these
factors has emerged as an alternative strategy for salvaging
ischemic cardiomyocytes.1–4 Although initial trials involving
the delivery of angiogenic factors, such as vascular endothe-
lial growth factor-A (VEGF-A), were associated with short-
term improvement, follow-up studies have yet to show long-
term benefits.5 Evidence for the role of bone marrow-derived
cells in angiogenesis has accumulated since endothelial
progenitor cells (EPCs) were identified and bone marrow-
or peripheral blood-derived EPCs have been recruited and
incorporated into the site of angiogenesis in the ischemic
tissue.6,7 In fact, a multicenter trial, the Therapeutic Angio-
genesis using Cell Transplantation (TACT) trial, showed that
autologous implantation of bone marrow-derived mono-
nuclear cells induced angiogenesis and improved clinical
parameters in patients with severe limb ischemia caused by
peripheral arterial disease.8 Since then, a number of clinical
studies have proven the efficacy and safety of autologous cell-
based therapy for ischemic heart disease, including MI.9–12
The results obtained from these clinical studies support the
important role of bone marrow-derived cells in angiogenesis.
However, because some clinical studies on ischemic heart
disease did not find the cell-based therapy to be significantly
beneficial,13,14 the efficacy of this therapy remains contro-
versial.
Chemokines are potent chemoattractant cytokines that
regulate leukocyte trafficking in homeostatic and inflamma-
tory processes.15 Depending on their topical concentration,
chemokines directly recruit circulating leukocytes to the site
of inflammation or injury. Many experimental and clinical
studies have demonstrated that a substantial number of
chemokines are involved in the pathophysiology of ischemic
heart diseases.16 Among them, stromal cell-derived factor-1α
(SDF-1α, also known as CXCL12α) is thought to play a key
role in angiogenic processes after MI. In particular, bone
marrow-derived cells, which express the SDF-1 receptor CXC
chemokine receptor 4 (CXCR4, also known as fusin and
CD184), have been shown to act as vascular stem/progenitor
cells (including EPCs) and promote angiogenesis after MI.
Furthermore, recent investigations showed that SDF-1α also
exerts direct cardioprotective effects after MI.17,18 This review
will focus on the role of the SDF-1/CXCR4 system in the
pathophysiology of MI and discuss whether this system is a
potential therapeutic target for MI. Although a large amount
of evidence indicates the role of the SDF-1/CXCR4 system
in the development of atherosclerosis in the coronary arteries,
which is the principal cause of MI, I will not discuss this
issue because several reviews on the same have already been
published.
Chemokines in MI
Chemokines
A number of components have been shown to be involved

Received December 22, 2009; accepted January 7, 2010; released online January 30, 2010
Division of Bioimaging Sciences, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan
Mailing address:  Masafumi Takahashi, MD, Division of Bioimaging Sciences, Center for Molecular Medicine, Jichi Medical Univer-
sity, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan.   E-mail: masafumi2@jichi.ac.jp
ISSN-1346-9843   doi: 10.1253/circj.CJ-09-1021
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.74,  March  2010

SDF-1/CXCR4 in MI 419

Figure 1.    Potential role of the SDF-1/CXCR4 system in myocardial infarction. At the site of tissue ischemia, such as the ischemic
myocardium, HIF-1α is induced in response to reduced oxygen tension and then stimulates SDF-1α expression. Binding of
SDF-1α to CXCR4 protects cardiomyocytes from apoptotic cell death. SDF-1α recruits bone marrow-derived stem/progenitor
cells and induces the production of angiogenic factors, thereby leading to angiogenesis. SDF-1α also simulates the migration of
endothelial cells and enhances angiogenesis. CXCR4, CXC chemokine receptor 4; HIF-1α, hypoxia-inducible factor-1α; SDF-1α,
stromal cell-derived factor-1α.

in the pathophysiology of MI. Among these, chemokines are
believed to be one of the key regulators because they are
expressed in the infarcted myocardium and also because
they play a crucial role in the process of myocardial inflam-
mation and healing.19 Chemokines have been divided into 2
main subfamilies on the basis of the conserved structural
features. In the CXC chemokines, a single amino acid is pres-
ent between the 2 amino-terminal cysteine residues. In con-
trast, in the CC chemokines, no amino acid is present between
the 2 cysteines. Other minor chemokine subfamilies that are
currently known include fractalkine/CX3CL1 (CX3C chemo-
kines) and lymphotactin/XCL1. The effects of chemokines
are mediated via their interaction with specific chemokines
receptors that are expressed on a wide range of cell types.
These chemokine receptors are 7-transmembrane (TM) G-
protein-coupled receptors and are unusual among the many
characterized members of the superfamily in that a single
receptor possesses multiple high-affinity ligands. Therefore,
initially, the chemokine network might appear to be a redun-
dant cellular signaling system; however, analysis of che-
mokines or gene disruption of their receptors in mice has
revealed that certain chemokines possess unique and non-
redundant roles in leukocyte trafficking, inflammation, and
immune responses.
The basic function of chemokines involves the regulation
of leukocyte trafficking in basal and inflammatory pro-
cesses. Recently, however, it has been observed that chemo-
kines are also expressed by non-hematopoietic cells such as
endothelial cells and cardiomyocytes, and their function
extends far beyond leukocyte migration and activation.16,20
Thus, chemokines are key mediators not only in inflamma-
tory responses but also in other responses involved in the
pathophysiology of ischemic diseases.
Chemokines in MI
Many experimental and clinical studies have shown that che-
mokines are involved in the pathophysiology of MI. The CXC
chemokines interleukin-8 (IL-8),21–24 SDF-1α25–27 GRO-α/
KC (known as CXCL1),22 and IP-10 and the CC chemo-
kines monocyte chemoattractant protein-1 (MCP-1, known
as CCL2)28,29 and macrophage inflammatory protein-1α/β
(MIP-1α/β, known as CCL3/4)30 appear to be upregulated
in various animal models of experimental MI. Two types of
MI models are currently used: the permanent MI model and
the ischemia–reperfusion (I/R) injury model. Several differ-
ent features exist between the pathophysiology of permanent
MI and I/R injury.31,32 Reperfusion releases a large excess
of reactive oxygen species (ROS) and causes “reperfusion
injury”. Inflammatory responses such as infiltration by neu-
trophils and macrophages are much stronger in the reperfused
heart than in the infarcted heart. Because the inflammatory
responses after MI determine tissue healing,19 collagen de-

Circulation Journal  Vol.74,  March  2010

420 TAKAHASHI M

Figure 2.    Therapeutic potential of the SDF-1/CXCR4 system for treating myocardial infarction. Several therapeutic strategies
using the SDF-1/CXCR4 system have been proposed: (1) local SDF-1α delivery and inhibition of SDF-1α cleavage, (2) up-
regulation of CXCR4 in cardiomyocytes and cardiac stem cells, (3) mobilization of CXCR4+ cells from the bone marrow into
peripheral circulation, or (4) upregulation of CXCR4 in bone marrow-derived cells and MSCs. CXCR4, CXC chemokine receptor
4; MSC, mesenchymal stem cells; SDF-1α, stromal cell-derived factor-1α.

position during MI may be accelerated in the reperfused
heart. Furthermore, neovascularization is more enhanced in
the reperfused heart than in the infarcted heart. Therefore, it is
necessary to consider the MI models used in different studies.
Consistent with the results of the experimental studies,
elevated serum concentrations of several chemokines were
observed in patients with MI,33 suggesting the clinical sig-
nificance of chemokines in the pathophysiology of MI.
The mechanisms responsible for the upregulation of che-
mokines in the infarcted heart have not been fully under-
stood. To date, however, it is known that several factors
implicated in initiating the inflammatory responses are likely
to induce the production of these chemokines. The induction
of IL-8 and MCP-1 is regulated by the transcription factor
NF-κB, which contributes to the regulation of inflammation
and is activated in the infarcted heart.34,35 Another important
transcription factor involved in MI is hypoxia-inducible
factor-1α (HIF-1α), which is induced by hypoxia (low O2
tension) and regulates VEGF induction. HIF-1αwas reported
to be in the active form in the infarct myocardium after MI
and induced SDF-1α in hypoxic conditions (Figure 1).36,37 In
addition to inducing SDF-1α, HIF-1α enhances the expres-
sion and function of CXCR4 in bone marrow-derived cells.
SDF-1/CXCR4 System in MI
SDF-1/CXCR4 System
SDF-1α and its receptor CXCR4, which is expressed at high
levels on both vascular and hematopoietic progenitor cells,
play a critical role in the development of the heart and blood
vessels and in the regulation of the motility and differen-
tiation in hematopoietic stem cells (HSCs). SDF-1, which
belongs to the CXC chemokine subfamily, is produced in
2 forms, SDF-1α (CXCL12α) and SDF-1β (CXCL12β), by
alternative splicing of the same SDF-1 gene.38 Different splic-
ing variants are characterized by distinct activities.39 SDF-1α,
which is the predominant isoform, is susceptible to pro-
teolytic degradation in the blood, whereas SDF-1β is more
resistant to this proteolytic process. SDF-1 binds to CXCR4,
G-protein-coupled receptors with 7 TM domains. The bind-
ing of SDF-1α to CXCR4 stimulates the dimerization of
the receptor and activates downstream signaling molecules,
including the activation of the focal adhesion kinase, extra-
cellular signal-regulated kinases, protein kinase C, JAK/Stat,
and NF-κB transcription pathways.40 The interaction between
SDF-1α and CXCR4 has been previously considered exclu-
sive, but it was recently identified that SDF-1α can also bind
with CXCR7.41,42
SDF-1α was initially isolated from bone marrow stromal
cells, and it is expressed in most normal tissues, such as
the heart, liver, spleen, and kidney, but not in leukocytes.
Different from other chemokines, which are induced by
inflammatory stimuli, the constitutive expression of SDF-1α
in bone marrow stromal cells suggests a fundamental role
in organ homeostasis and development. The experimental
deficiency of SDF-1α or CXCR4 in mice causes embryonic

Circulation Journal  Vol.74,  March  2010

SDF-1/CXCR4 in MI
lethality because of multiple defects, such as a cardiac ven-
tricular septal defect and the defective formation of the large
vessels in the gastrointestinal tract.43–45 In addition to these
defects, hematopoiesis is severely impaired, with deficien-
cies in the development of B cells, decreased myelopoiesis,
and HSC colonization of the bone marrow. Postnatally,
SDF-1α exerts various effects in a variety of cells, including
leukocytes, bone marrow stem/progenitor cells, and endothe-
lial cells. The main biological effects of SDF-1α are related
to its ability to induce chemotaxis, adhesion, motility, and the
secretion of matrix metalloproteinase (MMP) and angiogenic
factors,40 its involvement in the retention and recruitment of
bone marrow stem/progenitor cells, and its involvement in
the process of angiogenesis (Figure 1). SDF-1α also directly
stimulates endothelial cell migration and promotes angio-
genesis.20,46 Moreover, Jin et al reported that hematopoietic
cytokines stimulates the release of SDF-1α from platelets,
augmenting the recruitment of CXCR4+VEGFR1+ heman-
giocytes, thereby accelerating angiogenesis.47 Therefore, the
SDF-1/CXCR4 system is now recognized as playing an im-
portant role in a wide array of disease processes.
SDF-1/CXCR4 System in MI
SDF-1α has generated considerable interest for its role in
pathophysiology of MI. As mentioned earlier, the SDF-1/
CXCR4 system plays a critical role in cardiogenesis and
angiogenesis in the mouse embryo,43,44 indicating the role of
this system in adult cardiovascular diseases. Indeed, studies
conducted using various experimental models of MI show that
SDF-1α is upregulated in the ischemic myocardium.26,48–50
Although it is well known that the presence of SDF-1α is
essential in the ischemic myocardium, the value of serum
SDF-1αlevels is currently controversial. Chang et al recently
reported that although the serum levels of SDF-1α do not
differ between patients with acute MI and normal subjects;
patients with serious clinical conditions had significantly
higher serum SDF-1α levels than those in a relatively stable
condition and in normal subjects.51 They also showed that
increased levels of serum SDF-1α were significantly corre-
lated with an elevated number of circulating EPCs.
Therapeutic Implications
of the SDF-1/CXCR4 System
Since the SDF-1/CXCR4 system has been shown to have
not only cardioprotective effects but also angiogenic effects
in several experimental models of MI, this system can be a
therapeutic target for the treatment of MI (Figure 2). From a
historic point of view, the discovery of CXCR4 and its func-
tion as a coreceptor for the human immunodeficiency virus
(HIV) generated great interest in the development of small
molecular CXCR4 receptor antagonists for treating HIV
infection.52 In addition, the SDF-1/CXCR4 system might play
a role in the spread and progression of many different types
of malignancies.40 Therefore, several CXCR4 antagonists,
such as AMD3100, have been developed as agents for treat-
ing HIV infection and malignancies and shown to dramati-
cally increase the mobilization of CD34+ hematopoietic stem/
progenitors from the bone marrow into the peripheral circu-
lation in humans.53,54 However, it would be difficult to use
these agents for the treatment of MI because this may negate
their beneficial effects such as cardioprotection and angio-
genesis in the myocardium.
The modification of CXCR4 expression and function by
factors and/or conditions has been shown.12,40 For instance,
Circulation Journal  Vol.74,  March  2010
421
hypoxic preconditioning of cardiac stem/progenitor cells
(CLK: cardiosphere-derived, Lin– c-kit+ progenitor) upregu-
lates CXCR4 and increases the recruitment of these cells
into the ischemic myocardium, thereby reducing the infarct
size and improving the cardiac function after MI.55 On the
other hand, intravenous delivery of genetically modified mes-
enchymal stem cells (MSCs) expressing CXCR4 has shown
to improve cardiac function and remodeling after MI.56
Several factors such as C3a, hyaluronic acid, and soluble
vascular cell adhesion molecule-1 (VCAM-1) were recently
identified as priming agents of CXCR4+ cells and found
to increase SDF-1-dependent homing and engraftment of
HSCs.40 Recently, we demonstrated that cultivation spe-
cifically upregulated CXCR4 expression in bone marrow-
derived cells and the implantation of these cells enhanced
therapeutic angiogenesis and restored blood flow to the
ischemic tissue.57 In addition, a direct link between CXCR4
expression and angiogenic factor production was demon-
strated using bone marrow-derived cells isolated from CXCR4
hetero-deficient mice. On the other hand, the administration
of several factors, such as granulocyte colony-stimulating
factor (G-CSF), macrophage colony-stimulating factor, and
erythropoietin, has been shown to stimulate the mobilization
of CXCR4+ cells from the bone marrow to the peripheral
circulation and to exert beneficial effect in MI.58–60 Thus,
the modification of CXCR4 expression may enable the
enhancement of the angiogenic activity and homing capacity
of vascular stem/progenitor cells.
In terms of SDF-1α, the administration or adenoviral gene
transfer of SDF-1α into the injured myocardium improved
cardiac function and infarct size after MI through the anti-
apoptotic and angiogenic effects of SDF-1α.17,18 SDF-1α is
reported to exert its beneficial effects through 2 mechanisms:
inhibition of cardiomyocyte apoptosis and promotion of
angiogenesis (Figure 1). SDF-1α protects cardiomyocytes
from apoptotic cell death after hypoxic insult. This anti-
apoptotic effect is mediated by the PI-3 kinase/Akt signaling
pathway.18 On the other hand, SDF-1α recruits bone marrow-
derived stem/progenitor cells and induces the production of
angiogenic factors, thereby leading to angiogenesis. SDF-1α
also simulates the migration of preexisting endothelial cells
and enhances angiogenesis. Thus, SDF-1 has a therapeutic
effect in MI; however, there is a potential limitation to
the use of the SDF-1α protein because of its sensitivity to
cleavage by several proteases, including MMP-2 and CD26/
dipeptidylpeptidase IV (DPPIV). In this regard, Segers et al
recently designed a new chemokine called S-SDF-1 (S4V)
that is resistant to MMP-2 and DPPIV but retains its chemo-
tactic activity, and they showed that S-SDF-1 (S4V) delivery
promoted the recruitment of CXCR4+/c-kit+/Flk-1+ cells and
improved cardiac function after MI.61 More recently, Zaruba
et al demonstrated that combination therapy by using G-CSF
to mobilize EPCs from the bone marrow and DPPIV inhibi-
tion to prevent proteolytic cleavage of SDF-1α increased the
recruitment of EPCs to the infarct myocardium, and sub-
sequently improved cardiac function after MI.62 These find-
ings indicate that SDF-1α is a promising target for thera-
peutic interventions in MI. However, because SDF-1α is
produced in the ischemic myocardium and the chemotactic
effect of chemokines is generally regulated by their topical
concentrations,63–65 the precise effect of SDF-1αmay depend
upon the situation (ie, its local concentration, duration, and
time period after MI).
422
Conclusions
A large number of studies have suggested that chemokines
are key regulators of MI. Of these, SDF-1αis one of the most
important involved in the pathophysiology of MI. In this
review, I have discussed the role of SDF-1α and its receptor
CXCR4, which together constitute the SDF-1/CXCR4 sys-
tem, in the processes of MI and the role of this system as
a potential target in the treatment of MI. However, before
clinical application, further studies are necessary to elucidate
the precise role and mechanism of the SDF-1/CXCR4 sys-
tem in the pathophysiology of MI.
Acknowledgments
The author thanks Dr Uichi Ikeda and the members of the Division
of Cardiovascular Medicine, Shinshu University Graduate School of
Medicine for their invaluable support of this work. This work was partly
supported by research grants from the Ministry of Education, Culture,
Sports, Science and Technology, the Ministry of Health, Labor and
Welfare, and Takeda Science Foundation.
Disclosure
Conflict of Interest: none.
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