Abstract
Cardiovascular and metabolic diseases (CVMDs) are a leading cause of
death worldwide and imposes a huge socioeconomic burden on individuals
and healthcare systems, underscoring the urgent need to develop new drug
therapies. Developmental endothelial locus-1 (DEL-1) is a secreted
multifunctional domain protein that can bind to integrins and play an
important role in the occurrence and development of various diseases.
Recently, DEL-1 has attracted great interest for its pharmacological
role in the treatment and/or management of CVMDs. In this review, we
present the current knowledge on the predictive and therapeutic role of
DEL-1 in a variety of CVMDs, such as atherosclerosis, hypertension,
cardiac remodeling, ischemic heart disease, obesity, and insulin
resistance. Collectively, DEL-1 is a promising biomarker and therapeutic
target for CVMDs.
Keywords: DEL-1, cardiovascular diseases, metabolic diseases,
targets, therapeutics
Introduction
A wide range of diseases that affect the heart and blood vessels are
collectively referred to as cardiovascular diseases (CVDs), including
atherosclerosis (AS), myocardial infarction (MI), hypertension, cardiac
hypertrophy, and heart failure. Metabolic diseases, including diabetes,
obesity and non-alcoholic fatty liver disease, are closely related to
the occurrence and development of CVDs [1, 2]. Cardiovascular and
metabolic diseases (CVMDs) are the leading causes of death in the world,
which place a huge socioeconomic burden on individuals and healthcare
systems [3-6]. These diseases are caused by a combination of
multiple pathological factors, and their pathogenesis has not been fully
elucidated. Although effective primary prevention and treatment
strategies have reduced morbidity and mortality from CVMDs over the past
20 years, the prognosis of CVMDs remains unsatisfactory, and effective
interventions are still lacking [7, 8].
Immune cells and inflammatory responses are involved in all stages of
the occurrence and development of multiple CVMDs [9-11]. The
expression levels of various inflammatory mediators correlate with the
clinical diagnosis and prognosis of CVMDs [12-18].
Inflammation-related molecules such as interleukin-6 and growth
differentiation factor 15 have been identified as biomarkers of CVDs
[19]. Regulation of immune function and inflammatory response is an
important strategy for the treatment of CVMDs [20-24]. Increasing
evidences show that tissue-resident immune cells are involved in
regulating the pathophysiological processes of CVMDs [25-28]. Local
tissues, such as vascular endothelium and adipose tissue, also have an
important impact on the occurrence and development of CVMDs [29-32].
Various local tissues in the human body are not only passive targets of
immune and inflammatory responses, but also active regulators of
immunity [33]. Local tissue signaling can regulate immune cell
accumulation and functional plasticity and play a key role in
immune-driven CVMDs [34, 35]. Stromal and parenchymal cell-derived
signals (including growth factors, cytokines, and other locally acting
homeostatic factors) as well as intercellular adhesion interactions
mediate local tissue-to-immune communication in CVMDs such as myocardial
infarction [36-38]. The compartmentalized expression of tissue
signaling can facilitate optimal performance of cell-type-specific
effects and spatial regulation of immune responses. Therefore, it can be
speculated that homeostatic molecules in the tissue microenvironment at
different locations are critical for CVMDs.
Developmental endothelial locus-1 (DEL-1) is a secreted multifunctional
domain protein. As a local tissue signal, it exerts different regulatory
functions in different expression regions [39]. Endothelial
cell-derived DEL-1 mainly regulates the inflammation initiation by
inhibiting neutrophil recruitment, while macrophage-derived DEL-1
promotes the resolution of inflammation by enhancing neutrophil
apoptosis and macrophage efferocytosis [40]. There are increasing
evidences that the regulation of immune system homeostasis by DEL-1
plays an important role in CVMDs [41-43]. In this article, we review
the regulatory role of local tissue signaling DEL-1 in CVMDs, and look
forward to the future development of DEL-1 (Table 1).
Expression, structure and functions of DEL-1
Expression
DEL-1 is a 52KD multifunctional matrix protein encoded by EDIL3
(epidermal growth factor (EGF) like repeats and discoidin domains 3),
which was cloned and characterized in angioplasty cells and early
endothelial cells as early as 1998 [44]. Increasing evidences show
that DEL-1 is expressed in tissues such as the brain, lung, and gums
[39, 45, 46]. Some tissue-resident cells such as mesenchymal stromal
cells, macrophages, neuronal cells, osteoclasts and some hematopoietic
microenvironment cells can also secrete DEL-1 [39, 40, 47, 48]. The
mechanism regulating DEL-1 expression in tissues has not been
elucidated. The reciprocal regulatory role of IL-17 and DEL-1 is now
widely recognized (Figure 1). IL-17 directly inhibits endothelial DEL-1
expression, thereby promoting lymphocyte function-associated antigen 1
(LFA-1) -dependent neutrophil recruitment, while DEL-1 counteracts IL-17
production and IL-17-dependent inflammation [45, 49].
Mechanistically, IL-17 reduces DEL-1 expression in a glycogen synthase
kinase 3β (GSK3β)-dependent process that inhibits the binding of the key
transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) to the
EDIL3 promoter, thereby downregulating EDIL3 transcription. This
inhibitory action of IL-17 can be reversed at the GSK-3β level by
PI3K/Akt signalling induced by D-resolvins. Interestingly, DEL-1
expression gradually decreased with age, which may be related to the
increased expression level of IL-17 [39, 50]. Through interaction
with growth hormone secretagogue receptor (GHSR), erythromycin activates
JAK2 signaling, leading to DEL-1 transcription, which is MAPK
p38-mediated and C/EBPβ-dependent, as well as to PI3K/AKT-mediated
reversal of the GSK3β-dependent inhibitory effect of IL-17 on DEL-1
expression [51]. In another report, TNF reduced DEL-1 expression and
secretion in endothelial cells by reducing C/EBPβ binding to the DEL-1
promoter, while the steroid hormone dehydroepiandrosterone (DHEA)
reduced DEL-1 expression and secretion in endothelial cells by
activating tropomyosin receptor kinase A (TRKA) and downstream PI3K/AKT
signaling to counteract the inhibitory effect of TNF and restore C/EBPβ
binding to the DEL-1 promoter [52]. Furthermore, another independent
research group found that overexpression of the p53 response element
enhanced the transcriptional activity of EDIL3 [53]. Primary
endothelial cells isolated from p53 knockdown mice showed decreased
DEL-1 mRNA expression [53]. Furthermore, DEL-1 reciprocally enhanced
p53 expression in primary endothelial cells [53]. Therefore, these
findings suggest that Del-1 is a novel transcriptional target gene of
p53. In melanoma cells, inhibition of p38/MK2 signaling reduced DEL-1
expression, suggesting that DEL-1 may be a downstream target of MK2
[54]. In conclusion, the expression regulation mechanism of DEL-1 is
still imperfect and needs to be further explored.
Structure and function
DEL-1 comprises three N-terminal EGF-like repeats (E1, E2 and E3) and
two C-terminal discoidin I-like domains (C1 and C2) [44, 55]. The
RGD (Arg–Gly–Asp) motif in the second EGF-like repeat (E2) confers
DEL-1 the ability to interact with different integrins, including β2
(eg, αLβ2 and αMβ2) and β3 (eg, αvβ3) integrins [44, 56, 57]. The
discoidin I-like domain and glycosaminoglycan mediate the interaction of
DEL-1 with phosphatidylserine (PS) [40, 58]. These interactions in
turn confer important functions of DEL-1 in regulating immunity that
have a major impact on the initiation and resolution of inflammation,
raising the possibility that DEL-1 may be a promising therapeutic target
[39]. Specifically, the interaction of DEL-1 with αLβ2 or αMβ2
blocks the binding of the latter to its endothelial counter-receptor
intercellular adhesion molecule-1 (ICAM-1), thereby inhibiting leukocyte
adhesion and recruitment to sites of inflammation [46, 59]. With its
anti-inflammatory properties, DEL-1 can prevent a variety of
inflammation-related conditions, such as multiple sclerosis and lung
inflammation [45-48, 60, 61]. DEL-1 can capture platelet
microparticles by linking with PS and promote endothelial cell clearance
of microparticles in an αvβ3 integrin-dependent manner [62]. In
addition, DEL-1 can also act as a bridging molecule to bind PS on
apoptotic cells and αvβ3 integrin on macrophages at both ends, mediating
the burial of apoptotic cells and promoting inflammation resolution
[40, 63]. Collectively, DEL-1 exerts anti-inflammatory effects by
inhibiting neutrophil recruitment and migration, promotes inflammation
resolution by accelerating macrophage reprogramming, and regulates
myelopoiesis (Figure 2). These functions are discussed in detail in the
review by Hajishengallis et al, which is a work worthy of serious
reading [39, 64]. Experiments with various deletion mutants of DEL-1
showed that fragments containing the C-terminus of C1 with a lectin-like
structure were deposited directly in the ECM [58]. The deposition
efficiency varied according to the presence of other domains in DEL-1.
The fragment containing E3 and C1 had the strongest deposition activity,
while the fragment containing C2 was highly homologous to C1 and had low
deposition activity [58]. These data suggest that the Discoidin
domain of DEL-1 protein contributes to its deposition and function in
the extracellular matrix.
Genetic knockout or overexpressing mice of DEL-1 are an important tool
in studying the function of Del-1. EDIL3-/- mice have a specific
phenotype that is likely to develop spontaneous periodontitis [45].
DEL-1 deficiency promotes neutrophil infiltration and inflammatory bone
loss in periodontitis mice [45]. In experimental allergic
encephalomyelitis (EAE), DEL-1 deficiency increases immune cell
infiltration and inflammatory responses in the central nervous system,
leading to increased disease severity [47]. DEL-1 deficiency mice
exhibit increased neutrophil infiltration and inflammatory responses
during lung inflammation [46]. In postoperative peritoneal adhesion
(PPA) mice, EDIL3-/- mice had a higher incidence of PPA and increased
inflammatory response, resulting in more severe PPA [65].
Myelopoiesis in EDIL3-/- mice was suppressed in hematopoietic stem cells
(HSCs) [66]. The expression position of DEL-1 critically determines
its regulatory function. In the future, the application of different
transgenic mice with tissue- or cell-specific knockout or overexpression
of DEL-1 may better help us to study its function.
DEL-1 in CVDs
Atherosclerosis
As is a lipid-driven chronic inflammatory disease which underlies
various CVDs such as ischemic heart disease (IHD) [67-69]. The
formation of AS is caused by the accumulation and oxidative modification
of low-density lipoprotein (LDL) in the arterial intima [70]. As the
tissue microenvironment changes, endothelial cells release chemokines
and adhesion molecules, which promote the recruitment and migration of
monocytes on the endothelium; monocytes subsequently differentiate into
macrophages to phagocytose oxidized low-density lipoprotein (oxLDL),
while the excessive accumulation of oxLDL eventually leads to the
transformation of macrophages into foam cells and initiates the
secretion of inflammatory cytokines to promote the development of AS
plaques; at the same time, smooth muscle cells migrate to the
subendothelial to form fibrous caps and stabilize the plaques. Finn et
al. found that the serum level of DEL-1 in patients with coronary heart
disease (3.9 ± 0.2 pg/mg total protein) was significantly higher than
that in healthy subjects (2.9 ± 0.1 pg/mg total protein) [71].
However, there is still a lack of clinical evidence to prove that DEL-1
is related to the occurrence and development of AS.
In vitro evidence showed that DEL-1 can not only directly bind to oxLDL,
but also inhibit the uptake of oxLDL in cells transfected with multiple
scavenger receptor genes in a dose-dependent manner, such as lectin-like
oxidized low-density lipoprotein receptor-1 (LOX-1), scavenger receptor
A (SR-A), scavenger receptor class B type I (SR-BI), and the cluster of
differentiation 36 (CD36) [72]. DEL-1 inhibited the uptake of oxLDL
by human coronary artery endothelial cells (HCAEC) and macrophages.
Furthermore, the oxLDL-induced increase in monocyte chemotactic
protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM‑1)
expression in HCAECs was significantly inhibited by DEL-1, which has the
potential to alleviate monocyte adhesion. OxLDL-induced endothelin-1
secretion in HCAECs was also significantly inhibited by DEL-1 [72].
Therefore, Del-1 not only inhibited the binding of oxLDL to the
receptors, but also inhibited the cellular response to oxLDL.
In a mouse model of AS, DEL-1 overexpression inhibited receptor-binding
activity of a modified LDL in serum, reduced the expression of adhesion
molecules MCP-1 and ICAM-1 in the aorta, and reduced the oil red
O-positive atherosclerotic area at the aortic roots [72]. These
results suggest that DEL-1 overexpression inhibits the occurrence of AS.
However, in contrast to the above results, Subramanian et al.
constructed an AS model by partially ligating the left carotid artery in
ApoE−/− mice and found that endothelial cell-specific
overexpression of DEL-1 had no significant effect on the development and
cellular composition of AS plaques [73]. They fed
ApoE−/− mice a high fat diet for 4 or 12 weeks to
study early or late lesions and found that endothelial cell-specific
overexpression of DEL-1 did not affect early or late stages of AS and
did not prevent AS [73]. The apparent discrepancy between the
results of this study and that of Kakino et al. may be due to: 1. The
transgenic mice in Kakino et al.’s study overexpressed DEL-1 in all cell
types. In addition to the mechanism mediated by endothelial cell-derived
DEL-1, other mechanisms may also play a role, such as macrophages. 2.
Differences in experimental methods between the two studies may also
lead to conflicting results, such as differences in the background of
ApoE−/− mice, differences in HFD, differences in
modeling methods, and so on. In the future, transgenic mice with
macrophage-specific expression may help to further understand the role
of DEL-1 in AS.
Intercellular signaling plays a key role on AS formation, affecting the
occurrence and progression of CHD, and circulating microRNAs (miRNAs)
may be involved in this process [74]. There were clear differences
in circulating miRNA transport between CHD patients and healthy
subjects, especially the reduction in miRNA enrichment in microparticles
(MPs) [71, 75]. Furthermore, MPs from CHD patients were less
efficient at transferring miRNAs to cultured HUVECs, suggesting that MP
uptake is impaired in the disease state. DEL-1 can mediate the uptake of
MPs by endothelial cells by binding to PS on the external surface of MPs
[62, 63]. Although circulating levels of DEL-1 are increased in CHD
patients, these patients have less DEL-1 binding to MPs [71].
Therefore, Finn et al. suggest that DEL-1 binding to MPs was impaired in
CHD serum, thereby altering circulating miRNA transport and affecting
CHD initiation and progression. In the future, in addition to regulating
the expression of DEL-1, regulating the function of DEL-1 may also be an
important aspect in the treatment of AS.
Hypertension
Hypertension refers to a clinical syndrome characterized by increased
systemic arterial blood pressure (systolic and/or diastolic blood
pressure), which may be accompanied by functional or organic damage to
organs such as the heart, brain, and kidneys [76]. Hypertension is
the most common chronic disease and the main risk factor for
cardiovascular and cerebrovascular diseases [77]. Although the
pathophysiological mechanisms of hypertension are not fully understood,
strong evidences suggest that immune hyperactivation and chronic
inflammatory responses play a crucial direct role in the development of
hypertension [78]. Our team’s previous clinical and animal studies
also proved that immune microenvironment disturbances are closely
related to hypertension [79-83]. Activated T lymphocytes and
pro-inflammatory cytokines such as IL17 are involved in the occurrence
and development of angiotensin II (ANGII) and deoxycorticosterone
acetate-salt (DOCA-salt)-induced hypertension [84-89]. Gene knockout
or neutralization with antibodies of IL-17 limits the progression of
hypertension [86, 88, 90]. DEL-1 can inhibit inflammation through
various anti-inflammatory effects to address IL-17-mediated conditions,
such as inflammatory bone loss and multiple sclerosis, suggesting that
DEL-1 may be a potential target for the treatment of hypertension [45,
48]. Furthermore, DEL-1 promoted vascular smooth muscle cells (VSMC)
adhesion, migration and proliferation in a dose-dependent manner, which
were mediated through αvβ3 integrin
[91]. These data suggested that DEL-1 has a paracrine role in
vascular remodeling.
Recently, Failer et al found that endothelial DEL-1-overexpressing mice
had less adventitial collagen, lower medial thickness, and more elastin,
suggesting that DEL-1 overexpression prevents ANGII induced aorta
remodeling [41]. DEL-1 overexpression also prevented the progression
of ANGII-induced hypertension, endothelial dysfunction and aortic
fibrosis. DEL-1 overexpression alleviated the infiltration of CD45
leukocytes, TCR-β T cells and CD45IL-17 leukocytes in the aorta after
ANGII infusion. Meanwhile, DEL-1 overexpression also inhibited the
expression of pro-inflammatory cytokines induced by ANGII and increased
the expression level of the anti-inflammatory cytokine IL-10. In
addition to inflammation, DEL-1 overexpression inhibits the activity of
matrix metallopeptidase 2 (MMP2) in the aorta, whose increase critically
contributed to aortic remodeling in hypertension [92, 93].
Failer et al. next investigated the preventive and therapeutic effects
of recombinant DEL-1-FC on ANGII-induced hypertension. Intervention with
recombinant DEL-1-FC administered before or after hypertension prevented
or eliminated ANGII-induced aortic remodeling, hypertension, arterial
stiffness, and inflammation [41]. Recombinant DEL-1-FC also
inhibited the activity of MMP2 in the aorta while promoting the
infiltration of anti-inflammatory Tregs. Failer et al. also found that
the mutation of the RGE part of DEL-1 abolished the protective effect of
DEL-1-FC, suggesting that RGE is involved in the pathophysiological
process of DEL-1 inhibiting the occurrence and development of
hypertension. In a DOCA salt-induced hypertension model, recombinant
DEL-1 treatment similarly attenuated aortic remodeling, hypertension,
and inflammatory progression, and promoted Treg infiltration [41].
A series of in vitro experiments further demonstrated that DEL-1
overexpression and recombinant DEL-1 treatment inhibited ANGII-induced
activation of MMP2 in human and mouse vascular tissues, which was
αvβ3 integrin-dependent [41, 94].
Correspondingly, RGE mediates the binding of
αvβ3 integrin to DEL-1, which may
explain the abolition of the protective effect of DEL-1 by RGE mutation
[41, 56]. In conclusion, the findings of Failer et al. fully
demonstrate the protective role of DEL-1 in the occurrence and
development of hypertension, and may become a potential drug for the
treatment of hypertension in the future.
Cardiac remodeling
Cardiac remodeling is an independent risk factor for heart failure,
arrhythmias, and sudden death, and is a key determinant of the clinical
course and long-term prognosis of patients with CVDs [95].
Pathological cardiac remodeling is characterized by cardiomyocyte
hypertrophy and interstitial fibrosis under various cardiac stresses
such as hypertension and MI, resulting in increased myocardial stiffness
and impaired cardiac contractility [96, 97]. Cardiac remodeling is
associated with fibrosis, capillary sparseness, increased production of
proinflammatory cytokines, and cellular dysfunction (impaired signaling,
inhibition of autophagy, and abnormal cardiomyocyte/non-cardiomyocyte
interactions), as well as adverse epigenetic alterations [95]. Our
previous studies further shed light on the pathogenesis of cardiac
remodeling, suggesting that inhibition of cardiac remodeling by
pharmacological or genetic approaches significantly improves cardiac
dysfunction and survival [21, 98-101].
In mice, fibroblasts constituted 27% of all cardiac cells, contributing
to the maintenance of homeostasis under physiological conditions and
regulating tissue remodeling in response to stress [95, 102, 103].
Pathological fibrosis results from abnormal regulation of extracellular
matrix (ECM) production in tissues or organs, including collagen
[97]. Compared with normal lung tissue, the expression level of
DEL-1 was decreased in lung fibrous tissue, suggesting that DEL-1 may be
associated with pulmonary fibrosis [60]. Del-1 deficiency promoted
collagen synthesis and secretion by regulating transforming growth
factor (TGF-β), thereby aggravating bleomycin-induced pulmonary fibrosis
[60, 104]. Yan et al. found that DEL-1-deficient mice had a higher
incidence of postoperative peritoneal adhesions, accompanied by enhanced
collagen production [65]. In contrast, DEL-1 supplementation reduced
the incidence and severity of postoperative peritoneal adhesions. In
vitro studies demonstrate that DEL-1 inhibited TGF-β activation in 293T
cells and RAW264.7 mouse macrophages by binding to
αvβ6 integrin [104]. These data
suggest that DEL-1 plays an important role in the initiation and
progression of tissue fibrosis.
The immune system and inflammatory response mediate pathological cardiac
remodeling[97]. Immunomodulation may be one of the important
strategies to alleviate cardiac remodeling. Failer et al. found that
endothelial DEL-1 overexpression or recombinant DEL-1 treatment
inhibited AGNII or DOCA salt-induced inflammation and MMP2 activation in
the heart, thereby reducing cardiac hypertrophy, fibrosis, and
dysfunction [41]. However, cardiac remodeling in this study belongs
to target organ damage caused by hypertension, and the regulation of
DEL-1 on blood pressure may indirectly affect cardiac remodeling.
Therefore, this study may have certain limitations. Future studies on
cardiac remodeling may help us further understand the function of DEL-1.
Ischemic heart disease
Ischemic heart disease (ISHD), mainly caused by coronary atherosclerosis
and its complications, can induce congestive HF and life-threatening
arrhythmias, and is the leading cause of death worldwide [105, 106].
Acute myocardial infarction (AMI) is the most serious ISHD with the
highest mortality rate [106]. In a pig model of cardiac ischemia
induced by left circumflex artery ligation, DEL-1 treatment improved
cardiac function [107]. Wei et al. found that DEL-1 levels were
decreased in severe AMI patients, which is consistent with WT mice
following MI showing low levels of cardiac DEL-1 [42]. Compared with
WT mice, DEL-1-/- mice showed significantly improved
cardiac function and alleviated cardiac remodeling post-MI.
Mechanistically, the protective effect of DEL-1 deficiency in MI was
associated with enhanced neutrophil recruitment and expansion of
proinflammatory monocyte-derived macrophages [42]. Injection of a
neutrophil-specific C-X-C motif chemokine receptor 2 (CXCR2) antagonist
impaired macrophage polarization, increased cellular debris and
exacerbated adverse cardiac remodeling, thereby abrogating the
protective effect of DEL-1 deficiency. Inhibition of neutrophil
extracellular traps (NETs) formation by treatment with neutrophil
elastase inhibitor or DNase I abrogated differences in macrophage
polarization and cardiac function between WT and
DEL-1-/- mice after MI. Collectively, these data
suggest that DEL-1 is a key regulator of neutrophil recruitment and
macrophage polarization during cardiac remodeling after MI.
There is increasing evidence that healing of MI involves a series of
delicately regulated inflammatory responses [108]. Following MI,
injured cardiomyocytes release damage-associated molecular patterns
(DAMPs), cytokines, and chemokines, leading to massive recruitment of
neutrophils and monocytes/macrophages to the myocardium [109, 110].
These neutrophils and monocytes contribute to the removal of debris and
dead cells, as well as the activation of repair pathways. Furthermore,
recruited monocytes give rise to pro-inflammatory or repairing
macrophages. Pro-inflammatory macrophages produce cytokines, release
MMPs to promote extracellular matrix destruction, and clear cellular
debris, while repairing macrophages promote fibroblast-to-myofibroblast
transformation and enhance collagen deposition, leading to the formation
of cross-linked collagen [111]. A scar is formed to protect the left
ventricle (LV) from rupture of the heart. The study by Wei et al.
reiterates the integral role of inflammation in the healing process
[42]. However, excessive inflammation may exacerbate MI-induced
myocardial injury [109, 111]. DEL-1 has anti-inflammatory and
pro-resolving effects, and the lack of DEL-1 may inhibit inflammation
resolution, leading to excessive inflammatory response and aggravating
tissue damage [40, 60, 112, 113]. Therefore, the extent of the
increased inflammation caused by DEL-1 deficiency in Wei et al.’s study
requires further scrutiny.
The study by Wei et al. is the only report of amelioration of DEL-1
deficiency [42]. In previous reports, inhibition of neutrophil
recruitment improved cardiac dysfunction and cardiac remodeling after MI
[114-116]. Inhibition of neutrophils by DEL-1 also exerted
protective effects in other diseases, which seems to contradict the
study by Wei et al. [46, 48, 117]. Multiple actions of DEL-1 may
protect the heart from MI injury, such as anti- and pro-inflammatory
resolution [39], coronary vasodilation [41], inhibition of MMP2
activity [41] and promotion of angiogenesis [118, 119]. The
study by Wei et al. has certain limitations, such as the lack of
cell-specific gene-edited mice and not investigating the preventive or
therapeutic effects of recombinant DEL-1 [42]. The future use of
endothelial or macrophage-specific DEL-1 gene mice and recombinant DEL-1
may help us further understand the role and mechanism of DEL-1 in MI.
Other cardiovascular diseases
DEL-1 was found to regulate vascular morphogenesis or remodeling in
embryonic development as early as 1998 when it was first cloned and
characterized [44]. DEL-1 provided a unique autocrine angiogenic
pathway for the embryonic endothelium, which is mediated in part by the
integrin αvβ3 [120]. DEL-1 mediates
VSMC adhesion, migration and proliferation through interaction with
integrin integrin αvβ3, which may
regulate vascular wall development and remodeling [91]. Aoka et al.
found that DEL-1 accelerates tumor growth by promoting enhanced
angiogenesis [121]. Expression of endogenous DEL-1 protein is
increased in ischemic hindlimbs [122]. DEL-1 binding to
αvβ5 upregulated the expression of the
transcription factor Hox D3 and the integrin
αvβ3, thereby promoting angiogenesis and
functional recovery in a hindlimb ischemia model [57]. Exogenous
intramuscular administration of DEL-1 significantly enhances
angiogenesis in ischemic hindlimbs in mice, suggesting that DEL-1 may be
a novel therapeutic agent for ischemic patients [122]. A clinical
study compared VLTS-589 (a plasmid encoding Del-1 conjugated to
poloxamer 188) with poloxamer 188 control in the treatment of
intermittent claudication in patients with moderate to severe peripheral
arterial disease [123]. Intramuscular delivery of a plasmid
expressing DEL-1 and the control significantly improved baseline
exercise capacity at 30, 90, and 180 days, but there was no difference
in outcome measures between the two groups. DEL-1-mediated angiogenesis
has also been reported in many other diseases, such as ischemia models,
lung adenocarcinoma, retinopathy, squamous cell carcinoma, and psoriasis
[119, 124-129]. Taken together, these data suggest that
DEL-1-regulated angiogenesis may be a target for many diseases, but its
clinical value requires further clinical trials to demonstrate.
Similar to MI, strokes are also caused by vascular or microvascular
diseases that disrupt the blood supply to the brain, leading to brain
dysfunction [130]. The number of new vascular generated in ischemic
brain tissue is associated with decreased morbidity and longer survival
in stroke patients, suggesting that restoration of cerebral
microvascular circulation is important for functional recovery after
ischemic attacks [131]. The DEL-1 expression was increased in the
ischemic cortical peri-infarct area after ischemic stroke [118].
DEL-1 gene transfer induces cerebral angiogenesis and may provide a
novel and effective method for stimulating cerebral angiogenesis after
stroke [118]. Electroconvulsive seizures (ECS) have been shown to
treat major depression by modulating neurotrophy and angiogenesis
[132, 133]. Newton et al. found that ECS treatment increased DEL-1
expression in brain tissue and promoted angiogenesis in the adult rat
hippocampus [134]. In conclusion, DEL-1-mediated angiogenesis may be
one of the targets for the treatment of cerebrovascular diseases.
DEL-1 in metabolic diseases
The prevalence of metabolic diseases, including diabetes, is increasing,
while the westernization of dietary habits has led to an increase in
obesity [135]. Obesity-related chronic low-grade inflammation has
been reported to cause insulin resistance in muscle, liver, and adipose
tissue [136]. Insulin resistance refers to the decrease in the
efficiency of insulin to promote glucose uptake and utilization due to
various reasons, and the compensatory secretion of excessive insulin
produces hyperinsulinemia to maintain the stability of serum glucose
levels [137]. Insulin resistance predisposes to metabolic syndrome
and type 2 diabetes. DEL-1 ameliorates palmitate-induced endoplasmic
reticulum (ER) stress and insulin resistance in mouse skeletal muscle
cell line C2C12 via SIRT1/SERCA2-related signaling [43]. In vivo
experiments showed that DEL-1 administration increased the expression of
SIRT1 and SERCA2, thereby ameliorating insulin resistance in skeletal
muscle of high fat diet (HFD)-fed mice, and improving HFD-impaired
glucose tolerance and insulin sensitivity [43]. These results
suggest that DEL-1 may be a novel therapeutic target for the management
of insulin resistance and type 2 diabetes.
Regular exercise is the treatment of choice for obesity and
obesity-mediated metabolic disorders such as insulin resistance, type 2
diabetes, atherosclerosis, and hypertension [138]. Compared with
healthy subjects, the DEL-1 mRNA expression was decreased in the muscle
of obese and diabetic patients [139]. Exercise increases DEL-1 mRNA
expression levels in obese/diabetic patients in a time-dependent manner
[139]. DEL-1 secreted by exercising skeletal muscle can affect
various tissues through the bloodstream, including adipose tissue
[140]. In vitro experiments showed that DEL-1 attenuated
palmitate-induced inflammation and insulin signaling impairment in
adipocytes by regulating AMPK/HO-1 signaling [139]. In addition,
DEL-1 treatment also promoted AMPK phosphorylation and enhanced
adipocyte thermogenesis, but did not affect intracellular lipid
accumulation [139].
In another endometrial cancer (EC) cohort study, Cobb et al found an
association between patient BMI and increased DEL-1 expression in cancer
tissue [141]. Furthermore, HFD increased the expression of DEL-1 in
tumors compared with a low-fat diet in EC model mice [141]. These
data suggest that DEL-1 may serve as a novel obesity-driving target that
should be further explored in future research work.
Taken together, DEL-1-mediated anti-inflammatory and pro-resolving
effects provide a basis for amelioration of metabolic diseases. DEL-1
has been reported to be involved in the regulation of obesity and
insulin resistance. However, the current relevant evidence is still
insufficient, and more research is needed in the future to reveal the
role of DEL-1 in metabolic diseases.
Concluding remarks and future perspectives
DEL-1 has received considerable attention since it was first cloned and
characterized as a factor promoting embryonic angiogenesis [44].
DEL-1 is widely expressed in different tissues to maintain tissue
homeostasis, such as brain, lung and blood vessels. As a secreted
protein, the serum level of DEL-1 may be related to the diagnosis and
prognosis of various diseases, such as MI, sepsis and osteoarthritis
[42, 142, 143]. As a local tissue signal, DEL-1 exerts
anti-inflammatory and pro-resolving effects in different tissues and
stages, thereby ameliorating a variety of inflammation-related diseases
[39]. Emerging studies over the past few years have convincingly
demonstrated that DEL-1 has a therapeutic effect on a variety of CVMDs,
including AS, hypertension, cardiac remodeling, and insulin resistance.
This review summarized the potential involvement of DEL-1 in
cardiovascular and metabolic homeostasis, thereby defining DEL-1 as a
promising biomarker and therapeutic target for CVMDs.
Despite our detailed understanding of the role of DEL-1 in various
pathophysiological processes, several questions remain to be answered.
We proposed some solutions to these questions in this review. First,
systemic overexpression rather than endothelial cell-specific
overexpression of DEL-1 inhibited the occurrence and development of AS,
and the mechanism remains unclear [72, 73]. Other cells such as
macrophage-specific overexpression mice may help us understand the role
of DEL-1 in AS. Future basic research on the use of recombinant DEL-1 in
the treatment of AS can provide reference for its clinical application.
Second, although Wei et al. found that DEL-1 treatment attenuated
hypertension-induced cardiac remodeling, this protective effect may be
attributable to reduced blood pressure [41]. More direct evidence
for the treatment of DEL-1 in cardiac remodeling is lacking. The
application of other cardiac remodeling models could better reveal the
therapeutic effect of DEL-1 on cardiac remodeling. In vitro experiments
can also help us further understand the mechanism by which DEL-1
treatment improves cardiac remodeling. Third, DEL-1 deficiency
ameliorated cardiac dysfunction and remodeling in MI by promoting
inflammation [42]. Although the data in this study are sufficient,
we remain concerned about the extent of increased inflammation caused by
DEL-1 deficiency, as excessive inflammation is damaging. The future
treatment of DEL-1 overexpression or recombinant protein may help us to
further understand the role and mechanism of DEL-1 in MI.
The protective effect of DEL-1 in CVMDs has important clinical value.
There is currently only one phase II, multicenter, double-blind,
placebo-controlled study of DEL-1 in the treatment of intermittent
claudication, which combined a plasmid encoding DEL-1 with poloxamer 188
to form VLTS-589 and delivered intramuscularly [123]. Although the
outcomes of DEL-1 plasmid-treated patients did not change compared with
controls, this was an important attempt at clinical application of
DEL-1. Some researchers have also used DEL-1 for tissue engineering to
promote angiogenesis [119, 124]. On the one hand, we can use gene
therapy that promotes the expression of DEL-1 by constructing plasmids
for clinical experiments, and on the other hand, we can also use
nanomaterials and other technologies to deliver DEL-1 recombinant
protein or plasmids to target tissues, such as heart and brain. In
addition, well-designed, large-scale, high-quality, and multicenter
clinical trials are needed to evaluate the safety, toxicological
profile, and clinical utility of DEL-1 in human patients with CVMDs.
Collectively, DEL-1 is a promising biomarker and therapeutic target for
CVMDs.