Harnessing the early post-injury inflammatory responses for cardiac regeneration
Cheng et al. Journal of Biomedical Science
Harnessing the early post-injury inflammatory responses for cardiac regeneration
Bill Cheng 1
H. C. Chen 1
I. W. Chou 0 1
Tony W. H. Tang 1 2
Patrick C. H. Hsieh 0 1 2 3 4
0 Graduate Institute of Life Sciences, National Defence Medical Center , Taipei 114 , Taiwan
1 Institute of Biomedical Sciences , Academia Sinica, 128 Academia Road, Sec. 2Nankang District, Taipei 115 , Taiwan
2 Program in Molecular Medicine, National Yang Ming University , Taipei 112 , Taiwan
3 Department of Surgery, National Taiwan University Hospital , Taipei 100 , Taiwan
4 Graduate Institute of Medical Genomics and Proteomics, and Institute of Clinical Medicine, College of Medicine, National Taiwan University , Taipei 100 , Taiwan
Cardiac inflammation is considered by many as the main driving force in prolonging the pathological condition in the heart after myocardial infarction. Immediately after cardiac ischemic injury, neutrophils are the first innate immune cells recruited to the ischemic myocardium within the first 24 h. Once they have infiltrated the injured myocardium, neutrophils would then secret proteases that promote cardiac remodeling and chemokines that enhance the recruitment of monocytes from the spleen, in which the recruitment peaks at 72 h after myocardial infarction. Monocytes would transdifferentiate into macrophages after transmigrating into the infarct area. Both neutrophils and monocytes-derived macrophages are known to release proteases and cytokines that are detrimental to the surviving cardiomyocytes. Paradoxically, these inflammatory cells also play critical roles in repairing the injured myocardium. Depletion of either neutrophils or monocytes do not improve overall cardiac function after myocardial infarction. Instead, the left ventricular function is further impaired and cardiac fibrosis persists. Moreover, the inflammatory microenvironment created by the infiltrated neutrophils and monocytes-derived macrophages is essential for the recruitment of cardiac progenitor cells. Recent studies also suggest that treatment with anti-inflammatory drugs may cause cardiac dysfunction after injury. Indeed, clinical studies have shown that traditional ant-inflammatory strategies are ineffective to improve cardiac function after infarction. Thus, the focus should be on how to harness these inflammatory events to either improve the efficacy of the delivered drugs or to favor the recruitment of cardiac progenitor cells.
Heart regeneration; Inflammation; Macrophage
Myocardial infarction (MI) continues to be a major cause
of morbidity and mortality in many countries. In the
United States, MI is responsible for more deaths than
cancer and traffic accidents combined . Although
significant advances have been made in identifying
potential drug targets, there is still no specific treatment
that targets myocardial injury in patients with MI [2, 3].
An enormous body of evidence indicates that the
inflammatory responses that occur after MI play critical roles in
the overall cardiac output of the infarcted heart. Thus,
recent efforts by the scientific community and industry
have focused on understanding how the inflammatory
activities exerted by the recruited immune cells influence
the microenvironment of the infarcted heart in order to
achieve the desired clinical outcome.
Clinically, MI can be characterized into two main
phases, cardiac ischemia and reperfusion . In cardiac
ischemia, patients usually first experience onset of chest
pain at the moment that an occlusion has happened in
one of the coronary arteries. Subsequently, upon arrival
in hospital, patients receive thrombolytic therapy or
percutaneous coronary intervention to allow cardiac
reperfusion to happen. Even after oxygenation is
restored during reperfusion, cardiomyocytes still
experience cell apoptosis due to profound inflammation. Since
the adult mammalian heart has very little regenerative
capacity, the healing process of the infarcted
myocardium is dependent on the immune cells that are
recruited to the infarcted heart, which eventually lead to
the formation of a collagen-based scar. The main role of
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the scar is to replace the dead cardiomyocytes thereby
preserving the structural integrity of the left ventricles.
However, recent studies have shown that the recruited
immune cells, particularly monocytes and their
derivative, macrophages, release cytokines and proteases that
induce apoptosis in healthy cardiomyocytes. Thus, as
more cardiomyocytes undergo cell apoptosis, the size of
scar tissue increases, which is the cause of cardiac
fibrosis that is characterized by loss of cardiac muscle
elasticity and eventually heart failure.
Previously, anti-inflammatory therapeutics that target
the recruited monocytes have been considered as a
suitable therapy to prevent further weakening of the
myocardium after MI. In recent clinical trials, however,
many of the anti-inflammatory drugs such as Darapladib
failed to reach primary end-point . In addition, small
molecules like metformin were shown to induce
undesired side-effects in patients . Apart from poor drug
retention in the heart, it is becoming clear that the
immune cells also have reparative roles in heart healing.
Recent studies on lower vertebra, zebra fish and the
neonatal heart of mouse, have revealed that inflammation,
particularly caused by macrophages, is an essential
component of tissue regeneration [7, 8]. Depletion of
monocytes in neonatal mice before heart injury abolishes
subsequent organ regeneration, resulting in excessive
scarring and compromised cardiac function typical of an
adult response . Therefore, cardiac inflammation has
more complex roles than previously thought post-MI. In
this review, we focus on the roles of key immune cells
that participate in the early stage of healing after MI, as
well as novel strategies that utilize existing inflammatory
responses with an eye to achieving desired clinical
outcomes in patients with MI.
Immediately after cardiac ischemic injury, neutrophils
are the first innate immune cells recruited to the
ischemic myocardium within the first 24 h post-MI, especially
after reoxygenation is achieved. From a classic
immunological perspective, neutrophils are known to play critical
roles in preventing bacterial infection during the wound
healing process. Patients that have low neutrophil counts
or lack functional neutrophils often suffer from severe
bacterial and fungal infections after a non-sterile injury
has taken place . Physiologically, neutrophils are
programmed to undergo apoptosis after infiltrating into
the injured myocardium, in which the apoptotic
neutrophils attract macrophage recruitment and promote the
clearance of apoptotic cells in the injured tissue .
Therefore, in principle, these apoptotic neutrophils are
negative regulators of cardiac inflammation as
macrophages may remove cell debris by releasing
antiinflammatory factors such as IL-10 . In clinical
situations, however, the lifespan of neutrophils at the
infarct area is prolonged due to the effect of tumor necrosis
factor (TNF)-α and interleukin (IL)-1β . These
‘surviving’ neutrophils then secrete proteases such as
complement component C5a that promote cardiac remodeling
and chemokines that further potentiate leukocyte
recruitments. Moreover, the infiltrated neutrophils can also
induce apoptosis in healthy cardiomyocytes through the
release of reactive oxygen species (ROS).
Initially, neutrophils are guided to the injured
myocardium by the gradient of the released mitochondrial
damage-associated molecular patterns (DAMPs). Upon
the ischemic and reperfusion injury, ruptured cells
release all their cellular contents, including mitochondria
into the circulation. Since mitochondria and
mitochondrial DNA are structurally similar to their bacterial
counterparts, their presence in circulation is immediately
detected by neutrophils. Two of the neutrophil membrane
receptors, formyl peptide receptor 1 (FR1) and Toll-like
receptor 9 (TLR9) can recognize the presence of the
formylated peptide component of the mitochondrial
membrane and mitochondrial DNA, respectively . The
binding of the released mitochondrial components to
neutrophil receptors triggers neutrophil activation and
promotes cell extravasation into the injured myocardium.
Additionally, the mitochondrial DAMPs and other
released cellular components create a signaling gradient,
allowing the nearby neutrophils to precisely home to the
targeted site . DAMPs released by ruptured
cardiomyocytes also induce cardiac mast cell degranulation,
resulting in the release of contents such as histamine,
TNF-α, and IL-1β. These factors activate cardiac
endothelial cells, and induce the upregulation of membrane
surface receptors that facilitate neutrophil extravasation
through the endothelium to reach the targeted site.
Although neutrophils seem to have no direct role in
cardioprotection, lack of neutrophils results in worse
cardiac function and increased fibrosis and their
depletion does not accelerate heart healing after MI . It is
well-established that post-MI inflammation resolution is
characterized by the local conversion of pro-inflammatory
M1 macrophages into reparative M2 macrophages.
Traditionally, it has been thought that the M1/M2 stereotype
macrophages are influenced by the different ratio of
cytokines present in the myocardial microenvironment . A
more recent study, however, demonstrated that neutrophils
have a direct influence on the polarization of macrophages
after MI . In neutrophil-deficient mice with MI, it was
noticed that there was significantly fewer splenic Ly6Chigh
monocytes in the heart compared to the wild-type mice
with MI. Although there were more reparative M2
macrophages in the heart of neutrophil-deficient mice compared
to wild-type mice, these macrophages had reduced
expression of phagocytosis receptor
myeloid-epithelialreproductive tyrosine kinase (MertK) . MertK is a
marker of reparative M2 macrophages, which mediate
clearance of apoptotic cells. Thus, the low expression of
MertK in neutrophil-deficient mice results in insufficient
clearance of apoptotic cells by the reparative M2
macrophages, which leads to delayed inflammation resolution
after MI. Interestingly, circadian oscillations of neutrophil
recruitment to the heart also determine infarct size, healing,
and cardiac function after MI . The study revealed that
MI that happens during sleep-to-wake transition leads to
excessive cardiac neutrophil recruitment, larger infarct size,
and worsened heart function.
Monocytes and macrophages
Traditionally, it was thought that monocyte recruitment
happened immediately after neutrophils had infiltrated
the injured myocardium. However, intravital microscopy
of the beating mouse heart has shown that monocytes
are detected within 30 min after MI . Unlike
neutrophils, however, the number of monocytes being recruited
to the heart does not peak within the first 24 h post-MI.
Instead, immunohistological staining of heart tissue
sections of deceased patients revealed the maximum
number of monocytes being recruited to the heart happens
at 72 h post-MI . Moreover, the extravasation of
monocytes begins at the remote area, where healthy
myocardial tissue is present. Subsequently, the
monocytes migrate through the border zone and accumulate
at the infarct area. Such a migration pattern explains
why the targeting resolution of inflammation is a viable
therapeutic strategy in heart healing, since monocytes
are known to secret inflammatory cytokines and
proteases that are detrimental to cardiomyocytes . Thus,
if inflammation is prolonged, which is commonly seen
among patients with MI, the secreted factors will not
only further damage the surviving cardiomyocytes in the
infarct area, they will also harm the healthy
cardiomyocytes at the remote and border zones.
In the context of MI, monocytes recruited to the heart
in patients with MI can be divided into two
subpopulations, Ly6Chigh and Ly6Clow. The Ly6Chigh monocytes
are commonly known as pro-inflammatory monocytes,
whereas the Ly6Clow monocytes are sometimes known
as resident monocytes because of their capacity to
accumulate regardless of inflammation . Currently, it is
not clear which monocyte subset infiltrates the heart
immediately post-MI. However, it is well-established that
chemokine monocyte chemotactic protein (MCP)-1
drives the recruitment of Ly6Chigh monocytes to the
heart within the first 24 h post-MI . Days later, once
the inflammation is starting to resolve, the number of
Ly6Chigh monocytes in the heart or blood decreases,
whereas the number of Ly6Clow monocytes increases
. This conversion corresponds to the presence of
proinflammatory M1 macrophages in the heart early
after injury, and reparative M2 macrophages at the later
stage of heart healing . It is not certain whether M2
macrophages are trans-differentiated directly from M1
macrophages, or whether the trans-differentiation
requires the conversion from Ly6Chigh to Ly6Clow
monocytes. However, there is strong evidence that both the
Ly6Chigh and Ly6Clow monocytes arise from the same
progenitor cells , and that through a nuclear
receptor subfamily 4 group A member 1 (NR4A1)-dependent
transcriptional program, Ly6Chigh monocytes
differentiate into Ly6Clow monocytes .
In humans, cardiac monocytes are also classified into
two subsets based on the expression level of CD14 and
CD16. The CD14+ CD16− and CD14+ CD16+ monocytes
are the human analogues of mouse Ly6Chigh and
Ly6Clow monocytes, respectively. Clinical data indicate
that at the early stage of MI in human patients, ~85% of
the monocytes detected in the heart are CD14+ CD16−
monocytes which exhibit pro-inflammatory activity .
Similar to the time course seen in the murine model of
MI, as the inflammation resolves the monocyte
population starts to shift towards the CD14+ CD16+ subset
. It was demonstrated that at 5-7 days post-MI, 60%
of CD14+ CD16− and 40% of CD14+ CD16+ are
accumulated in the infarct area .
Cardiac resident macrophages
Previously, it was thought that the profound
inflammation that happens in the heart after MI is heavily
influenced by the recruited monocyte-derived macrophages.
However, recent studies have demonstrated the existence
of cardiac macrophages derived from embryonic
precursors that are termed resident macrophages . Unlike
the monocyte-derived macrophages, cardiac resident
macrophages are established in the heart during
embryonic development and are easily detected at E10.5 .
Furthermore, these resident macrophages are yolk
sacderived since they are detected in the heart prior to fetal
liver hematopoiesis . Similar to other embryonic yolk
sac macrophages in other tissues, cardiac resident
macrophages have the expression pattern MHC-IIlow,
CX3CR1high, F4/80high, and CD11blow. Studies on the
healthy heart of CX3CR1GFP/+ mice reveal a large
number of macrophages are in direct contact with myocytes
and endothelial cells . Under non-pathological
conditions, cardiac resident macrophages are considered
non-inflammatory. The cells have low expression level of
Ly6C markers and have a set of 22 upregulated genes
(including Mrc1, CD163, and Lyve-1) that are
characteristics of activated M2 macrophages . Interestingly,
cardiac resident macrophages are also found to express
some inflammatory genes, including IL-1β, which
highlights the limitations of the M1/M2 classification .
The function of cardiac resident macrophages in healthy
heart is still under investigation, although it has been
speculated that these cells may be involved in preventing
bacterial infection, regulating angiogenesis, and matrix
protein turnover .
The resident macrophages within the heterogeneous
population of macrophages in the infarcted heart can be
distinguished by the expression level of the surface
marker CCR2 . Unlike the monocyte-derived
macrophages, cardiac resident macrophages have very low
level of expression of CCR2. The chemokine receptor,
CCR2, also known as CD192, is a key receptor that
facilitates monocyte extravasation through the recognition of
MCP-1 . Studies of the proliferation marker Ki-67
revealed that cardiac resident macrophages undergo
rapid proliferation to increase their numbers in the heart
after MI, whereas no proliferative activity is detected in
the recruited monocytes after they differentiate into
macrophages . Although monocyte-derived
macrophages play important roles in coordinating cardiac
inflammation, their roles in antigen sampling and
efferocytosis are less critical than the resident macrophages
. Mice that lack circulating monocytes are found to
have fewer inflammatory activities associated with
cardiac pathology after injury , suggesting that excessive
expansion of macrophage populations can have a
detrimental effect on heart healing. Additionally, the loss of
Ly6Chigh monocytes also prevents hypertension-induced
cardiac fibrosis and improves left ventricle function after
MI . Indeed, it has been found that cardiac resident
macrophages are more efficient at removing apoptotic
cardiomyocytes, thus promoting the resolution of
cardiac inflammation . Like the reparative M2
macrophages, the resident macrophages also have a high
expression level of MertK, and the loss of this receptor
leads to increased neutrophil persistence and decreased
level of IL-10 in the myocardium . Thus, a good
anti-inflammatory strategy for treating patients with MI
in the future would be to selectively target the recruited
monocytes, without affecting the activity of resident
Macrophages and endogenous stem cells
Since adult mammalian hearts have poor regenerative
capability, the ultimate goal of any cardioprotective
treatment is to achieve a substantial level of cardiac muscle
regeneration. Genetic fate-mapping study of adult murine
hearts demonstrates that there are stem cells or precursor
cells present in the heart that contribute to the
replacement of adult mammalian cardiomyocytes after
myocardial infarction . As also highlighted above, two
populations of macrophages, M1 and M2, participate in
creating the phase 1 (day 1-3 after MI) and phase 2 (day
4-7 after MI) inflammatory microenvironments in the
infarct area respectively [39–41]. The M1 macrophages
that are dominant in phase 1 of MI phagocytose cell
debris in the infarct zone and secrete pro-inflammatory
cytokines, such as TNFα, IL1β, IL6 and IL10 . In contrast,
M2 macrophages, the major macrophages in phase 2 of
MI, promote collagen deposition and angiogenesis to the
infarct area . The inflammatory microenvironments
not only activate cardiofibroblasts for myocardium
remodelling, but also activate endogenous stem cells for
heart regeneration, either by cell fusion or
transdifferentiation [42–44]. Despite that the endogenous cardiac
progenitor cells (CPCs) are activated in response to heart
damage [42, 43], nevertheless an as yet unclear interaction
between CPCs and macrophages in the infarct area
remains to be elucidated. One key factor that bridges CPCs
and macrophages in the injured heart is prostaglandin E2
(PGE2), whose release from the injured heart regulates
macrophage populations and exerts a salutary effect on
the myocardium [45–47].
PGE2 in the injured site binds to the G
proteincoupled receptor E prostanoid 2 (EP2) on monocytes to
suppress the maturation of these monocytes to M1
macrophages through activating the downstream cyclic AMP
(cAMP)/protein kinase A (PKA) signalling . PGE2
also activates EP2/EP4 receptors, which induce
upregulation of cAMP and its downstream cAMP responsive
element binding (CREB)/transcriptional coactivators 2
and 3 (CRTC2/3)-mediated induction of Krupple like
factor 4 (KLF4) to promote polarization of M2
macrophages . Therefore, strategies modulating the balance
of M1/M2 macrophages such as by PGE2 treatment may
create a favourable inflammatory microenvironment in
the infarct zone to promote heart repair and
regeneration after MI [40, 49].
Harnessing early cardiac inflammation
Despite its poor clinical outcome in recent trials in
patients with MI, anti-inflammatory therapeutic strategy
is still considered to be a viable option for controlling the
size of the infarcted area. From the recent advances in
understanding the roles that the innate immunity plays in
post-MI, it is increasingly clear that downregulating the
inflammatory activity exerted by recruited
monocytederived macrophages would promote better cardiac
output in patients with MI . Since macrophages have
different roles at different time points after MI, future
therapeutic strategies should focus on minimising the
inflammatory effects rather than completely inhibiting the
entire inflammatory activities. Thus, an ideal treatment
should be able to assist the recruited immune cells to
create an inflammatory microenvironment that is favourable
for cardiac regeneration but with minimal
interferences to their inflammatory activities at a specific
time point. Here, we present two therapeutic strategies
that harness the inflammatory events that happen after
MI to achieve cardioprotection and to improve cardiac
Biomimicking platelet-monocyte interactions
Similar to other cardioprotective drugs, anti-inflammatory
therapeutics that are designed for cardioprotection in the
heart have poor targeting for the organ itself. Although
these drugs have high specificity for their designed targets,
they have poor retention in the heart after MI.
Consequently, poor targeting has been a key reason that explains
why some of these drugs could not be translated into
clinical practice . The issue of poor targeted drug delivery
for infarcted hearts is evident by a recent clinical trial of
cyclosporine in patients with MI . Despite the drugs
were encapsulated in PEGylated liposomes, the results
from the trial revealed that most of the administered
cyclosporine was distributed in other organs rather than
in the heart. Poor drug targeting not only cannot improve
overall cardiac output, but also can induce undesired
sideeffect in other organs . Thus, there is an urgent need
to develop a novel delivery strategy that can maximize the
overall efficacy of the delivered drugs for cardioprotection.
It has recently been proposed that platelet-like
proteoliposomes (PLPs) that can biomimic platelet interactions
in circulating monocytes act as a novel way of delivering
anti-inflammatory drugs to the infarcted heart .
Clinically, platelets are found to interact with surfaces of
the recruited monocytes in patients with MI to form
platelet-monocyte aggregates, which have been used as
an early detection biomarker and for monitoring the
progression of the disease . The biological
significance of the binding between platelets and monocytes is
still not known, but it has been suggested to facilitate
monocyte extravasation into tissue . Similar to
circulating platelets, PLPs show strong binding affinity for
monocytic cell lines, but not for endothelial cells. More
importantly, PLPs are able to infiltrate into the infarct area
in large number by anchoring on the surfaces of the
recruited monocytes. Therefore, in this monocyte-mediated
delivery strategy, the host monocytes are used as “shuttle
buses” to carry the PLPs and their cargoes directly to the
heart (Fig. 1). Such a delivery strategy is more effective
than the current delivery strategy which relies on the
presence of an enhanced permeability and retention (EPR)
effect . A recent study on nanoparticle distribution in
the murine model of I/R has revealed that EPR effect
starts to diminish after 24 h post-infarction , which
explains why so many cardioprotective drugs have poor
retention in the heart. Therefore, unlike in cancer, EPR
effect only exists for a short duration after MI, which is
insufficient for meaningful cardioprotection and preventing
remodelling, which takes place over days to weeks.
Another advantage of the monocyte-mediated strategy
is the selectivity for the recruited monocyte-derived
macrophages. Since PLPs could only infiltrate the infarcted
heart through interactions with recruited monocytes, the
particles themselves are immediately phagocytized by the
recruited monocyte-derived macrophages upon entering
the myocardium. Consequently, PLPs have less chance to
Fig. 1 Platelet-like proteoliposomes enhance the targeting specificity for infarcted heart through biomimicking platelet interactions with circulating
monocytes. (1) Platelets adhere to the surface of recruited monocytes during the development of MI. (2) Accordingly, platelet-monocyte aggregates
will undergo extravasation. (3) It is hypothesized that platelet-like proteoliposomes (PLPs) will interact with monocytes in a similar way to platelets. (4)
Once crossing the endothelium, the PLPs are expected to be phagocytized by monocyte-derived macrophages
contact with the cardiac resident macrophages after
MI, allowing the encapsulated drugs to release within
the recruited monocyte-derived macrophages only.
This monocyte-mediated strategy has opened up a
new paradigm in drug delivery, as it is the first
reported case of EPR-independent drug delivery to the
heart, and that the delivery vehicle specifically targets
the recruited monocytes.
PGE2 and M2 macrophage polarization
Traditionally, PGE2 is considered a proinflammatory
molecule. However, it has recently been suggested that
PGE2 may modulate the inflammatory
microenvironment for tissue regeneration through regulating
macrophage subtypes . Intraperitoneal injection of PGE2 in
a murine model of MI has been shown to promote
replenishment of cardiomyocytes from endogenous CPCs
Fig. 2 Effects of prostaglandin E2 on macrophages, cardiomyocytes and cardiac progenitor cells after myocardial infarction. Ly6Chigh monocytes
undergo maturation to generate M1 macrophages during the phase 1 of inflammation in the infarct area and perform phagocytosis to clean cell
debris and produce pro-inflammatory cytokines TNFα, IL1β, IL6 and IL10. Maturation of M1 macrophages is inhibited by PGE2 via the EP2/cAMP/
PKA pathway. Ly6Clow monocytes undergo M2 macrophage polarization during the phase 2 of inflammation which is promoted by PGE2 through
the EP(2/4)/cAMP/CREB/CRTC(2/3)/KLF4 pathway
by down-regulation of TGF-β signalling in cardiomyocytes
. The effect of PGE2 on CPCs is mediated through
interaction with the EP2 receptor . However, the
molecular mechanism underpinning the TGF-β-mediated
salutary effect of PGE2 on CPCs is unclear. One possible
mechanism is through inhibition of the TGF-β/TGF-β type
2 receptor (TβR2)/TGF-β-activated kinase 1 (TAK1)
signalling in cardiomyocytes, which leads to upregulation of bone
morphogenetic protein 7 (BMP7) and thus suppresses
fibrosis in injured hearts . Another possible mechanism
may be attributed to the production and release of
protective cardiokines from the cardiomyocytes to enhance the
survival of cardiomyocytes after injury. The evidence comes
from the mice with cardiomyocyte-specific knockdown of
TGFβR1, which show dramatic elevation of protective
cardiokine IL-33, growth and differentiation factor 15
(GDF-15) and thrombospondin 4 (Thbs 4) after MI .
The elevation of these protective cardiokines reduces the
apoptosis of cardiomyocytes in the infarct area and
improves the survival of mice after MI. The advancing effect
of PGE2 on cardiomyocyte replenishment may also be
related to the function of PGE2 in promoting proliferation of
adult stem cells [60, 61]. Administration of PGE2 to human
mesenchymal stem cells maintains proliferation and
selfrenewal of these cells via the EP2 receptor which then
enhances the production and autocrine effect of PGE2 itself
. Moreover, human cardiomyocytes stimulated with
thrombin triggers the production of PGE2, which in turn
promotes cardiomyocyte proliferation via EP2 receptors
. Whether PGE2 exerts the same proliferative effects on
CPCs in the ischemic hearts requires further investigation.
The function of PGE2 during inflammation and cardiac
regeneration is illustrated in Fig. 2.
Cardiac inflammation continues to be a viable drug target
for future development of therapeutics for
cardioprotection. Paradoxically, the inflammatory events that happen
after MI can either induce undesired inflammatory
responses that cause long term weakening of myocardium
or remodel the microenvironment that is favourable for
cardiac repair. Accordingly, traditional anti-inflammatory
strategy is no longer feasible to achieve desired clinical
outcome. Future therapeutic approaches should focus on
harnessing the inflammatory events to achieve better drug
efficacy, as well as modulating the inflammatory
microenvironment favourable for cardiomyocyte replenishment.
BMP7: Bone morphogenetic protein 7; cAMP: cyclic AMP; CPC: Cardiac
progenitor cell; CPC: Cardiac progenitor cell; CREB: cAMP responsive element
binding; CRTC: CREB transcriptional coactivators; DAMP: Damage-associated
molecular pattern; EP: G protein-coupled receptor E prostanoid;
GDF5: Growth differentiation factor 5; IL: Interleukin; KLF4: Kruppel like factor
4; MertK: Myeloid-epithelial-reproductive tyrosine Kinase; MI: Myocardial
infarction; PGE2: Prostaglandin E2; PKA: Protein Kinase A; PLPs: Platelet-like
proteoliposomes; TAK-1: TGF β-activated kinase 1; TGF-β: Transforming
growth factor-β; Thbs4: Thrombospondin 4
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