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eISSN: 1875-6212

Current Vascular
Pharmacology
The journal for current and in-depth reviews on Vascular Pharmacology

Pharmacological Therapy of Abdominal Aortic Aneurysm: An Update Impact

Factor:
2.391

BENTHAM
SCIENCE

Yi-dong Wang1, Zhen-jie Liu2, Jun Ren3 and Mei-xiang Xiang1,*

1
Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Cardiovascular Key
Lab of Zhejiang Province, #88 Jiefang Road, Hangzhou, Zhejiang, 310009, P.R. China; 2Department of Vascular Sur-
gery, Second Affiliated Hospital of Zhejiang University School of Medicine, #88 Jiefang Road, Hangzhou, Zhejiang,
310009, P.R. China; 3Department of Surgery, University of Wisconsin - Madison, Madison, WI, USA

ARTICLE HISTORY
Received: February 03, 2017
Revised: March 24 2017
Accepted: March 26, 2017
DOI:
10.2174/1570161115666170413145705
Current Vascular Pharmacology
Abstract: Background: Abdominal aortic aneurysm (AAA), a progressive segmental abdominal aortic
dilation, is associated with high mortality. AAA is characterized by inflammation, smooth muscle cell
(SMC) depletion and extracellular matrix (ECM) degradation. Surgical intervention and endovascular
therapy are recommended to prevent rupture of large AAAs. Unfortunately, there is no reliable pharmacol-
ogical agent available to limit AAA expansion. In the past decades, extensive investigations and a body of
ongoing clinical trials aimed at defining potent treatments to inhibit and even regress AAA growth.
Conclusion: In this review, we summarized recent progress of potential strategies, particularly macrol-
ides, tetracyclines, statins, angiotensin converting enzyme inhibitors, angiotensin receptor blocker, cor-
ticosteroid, anti-platelet drugs and mast cell stabilizers. We also consider recently identified novel mo-
lecular targets, which have potential to be translated into clinical practice in the future.

Keywords: Abdominal aortic aneurysm, clinical trials, medical treatment, pharmacological therapy, molecular target, disease.

1. INTRODUCTION 2. CURRENT MEDICAL TREATMENTS FOR AAA

Abdominal aortic aneurysm (AAA), a progressive ab-
dominal aortic dilation due to various life-style and genetic
factors, is associated with high mortality. The incidence of
AAA is up to 8% in man over 65 years old [1, 2]. In the
United States, AAA rupture and complications after sur-
gery caused at least 15,000 deaths/year, and the actual
number of deaths may double considering those without
diagnosis [2].
Although significant progress has been achieved in
AAA imaging as well as in open and endovascular repair,
effective pharmacological treatments (i.e. for the preven-
tion of AAA occurrence, and expansion, rupture as well as
perioperative treatment of AAA) are still unavailable
(Table 1). Current evidence of medical therapy is low-
quality, and no effective and specific target has been found
for AAA, likely due to incomplete understanding of the
biological mechanisms underlying the disease. Therefore,
surgical intervention is the optimal treatment for patients
with AAA. Herein, we review the most up-to-date pharma-
cological treatments for AAA and consider some potential
target molecules.
*Address correspondence to this author at the Department of Cardiology,
Second Affiliated Hospital of Zhejiang University School of Medicine,
Hangzhou, China; Tel: +86-13588035801; E-mail: xiangmxhz@163.com
2.1. Macrolides and Tetracyclines
Macrolides, roxithromycin and azithromycin, can
potently combat various infections including Chlamydia
pneumonia (C. pneumonia). It has been reported that C.
pneumonia is associated with AAA formation [3]. Thus, an-
tichlamydial treatment is a putative way to control AAA.
Administration of roxithromycin 300 mg daily for 4 weeks
significantly decreased AAA expansion compared with pla-
cebo treatment in the 1.5 year follow-up [3]. Furthermore, a
long-term effects of roxithromycin were evaluated [4]. Pa-
tients were treated with roxithromycin 300 mg daily for 4
weeks annually and followed up for average 5.27 years.
Consistently, treatment of roxithromycin reduced annual
growth rate, namely 36%, and lowered the risk of surgical
repair [4]. Nevertheless, a randomized double-blind con-
trolled trial demonstrated that azithromycin hardly inter-
vened AAA expansion, suggesting a limited role of macrol-
ides in AAA treatment [5]. Elimination of C. pneumonia
seems not to fully account for the effectiveness of roxithro-
mycin. The underlying mechanisms needs to be explored in
the future.
The role of doxycycline in AAA was extensively dis-
cussed in a recent review [6]. In elastase- or angiotensin
(Ang) II-induced AAA models, doxycycline strongly inhib-
ited AAA formation, but it had little effect on established
AAAs [6, 7]. The effects of doxycycline on AAA were origi-

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Pharmacological Therapy of Abdominal Aortic Aneurysm Current Vascular Pharmacology, 2018, Vol. 16, No. 2 115

Table 1. Recent randomized clinical trials of AAA medical treatments.

Medication Target Intervention Primary Outcome Trial Registration Status

ACZ885 IL-1 Subcutaneous ACZ885 (monthly) vs placebo AAA growth by ultrasound NCT02007252 Terminated

Telmisartan RAS system Telmisartan (40 mg daily) vs placebo AAA growth by CTA NCT01683084 Active

Perindopril Perindopril arginine (10 mg daily) vs amlodip-

RAS system AAA growth by ultrasound NCT01118520 Completed
arginine ine (5 mg daily) vs placebo

Ticagrelor Platelet Ticagrelor (90 mg daily) vs placebo AAA growth by MRI NCT02070653 Recruiting

Allogeneic T-regulatory 1 million allogeneic MSCs/kg vs 3 million Incidence of treatment Not yet
NCT02843854
MSCs cells allogeneic MSCs/kg vs placebo (Plasmalyte A) related adverse events recruiting

Doxycycline MMPs Doxycycline (100 mg twice daily) vs placebo AAA growth by CT NCT01756833 Recruiting

-adrenergic
Atenolol and Atenolol (50 mg daily) vs valsartan
receptor and AAA growth by CT NCT01904981 Recruiting
Valsartan (80 mg daily)
RAS system

CRD007 (10 mg twice daily) vs CRD007 (25

CRD007 Mast cell mg twice daily) vs CRD007 (40 mg twice AAA growth by ultrasound NCT01354184 Completed
daily) vs placebo

Aliskiren and RAS system and Aliskiren (150 mg daily) vs amlodipine Aneurysmal vessel wall
NCT01425242 Terminated
amlodipine calcium channel (5 mg daily) inflammation by PET-CT

originally attributed to its effect on matrix metalloproteinases
(MMPs) activity reduction by competitive binding zinc co-
factor. New insight theory proposed that doxycycline possi-
bly decreased T cell expansion during AAA growth [6]. Sev-
eral small clinical trials supported the inhibitory effects of
doxycycline on AAA. However, a recent large, randomized,
placebo-controlled, double-blind trial challenged this idea [6-
8]; 286 patients who were treated with 100 mg doxycycline
daily for 18 months did not gain benefit during AAA pro-
gression. However, they had a higher AAA expansion rate.
The insufficient dose, 100 mg daily, may responsible for the
negative result. Another phase IIb, randomized, double-blind
trial with 200 mg daily is still on-going, and their newly pub-
lished paper indicated that data advocates the hypothesis that
AAA development declined by 40% [9]. The ultimate con-
clusion of this trial will potentially provide solid evidence for
clinical practice.
2.2. Statins
Emerging evidence suggested that statins are promising
candidates in AAA medical therapy. Several studies in mur-
ine models reported that statin administration decreased
AAA growth, but Iida et al. declared a negative outcome [10,
11]. The influence of statins on AAA may be multifactorial
involving suppression of inflammation and ECM remodeling
in addition to their lipid-lowering capability [12, 13]. In hu-
man AAA specimens, administration of simvastatin or
atorvastatin greatly depressed vascular wall inflammation,
reflected by decreased nuclear factor-B (NF-B) activity
and its downstream cytokines, interleukin (IL)-6 and mono-
cyte chemotactic protein (MCP)-1 [14, 15]. Furthermore, a
recent study suggested that simvastatin treatment also regu-
lated MMPs and their inhibitors, namely tissue inhibitor of
metalloproteinases (TIMPs) in human AAA tissues and
thrombi [16].
A body of observational clinical studies indicated that
AAA patients on statins had a lower growth rate, compared
with non-statin users [17-20]. Nevertheless, another four in-
vestigations, as Dunne concluded, failed to detect a difference
in AAA growth between statin users and non-users [17].
These discrepancies might stem from different AAA meas-
urements. Although a variety of meta-analyses of this topic
suggested that statin therapy was related to less AAA dilation,
this conclusion relied on low-quality evidence [21-25]. To
confirm the roles of statin in limiting AAA expansion, a large
randomized trial is required in the future. Regardless of effects
of statins on AAA expansion, several early studies claimed
that these drugs effectively improved the outcome of patients
with vascular surgery [26-28]. In a nationwide, case-control
study, statins significantly lowered 30-day mortality rate of
ruptured AAA patients [29]. Promisingly, continuous statin
treatment during the perioperative and postoperative period in
the long run increased survival after open or endovascular
aneurysm repair (EVAR) and reduced incidence of complica-
tions [30-32]. Following up patients after surgery for 6 years,
de Bruin's work revealed that statin use is independently asso-
ciated with better outcome after AAA repair [32]. It has also
been reported that statin treatment intended to regress the
AAA sac after EVAR, though no significant difference was
observed compared to the group without statin [33, 34]. There-
fore, the available evidence suggests that statins should be
recommended for AAA patients.
2.3. Angiotensin Converting Enzyme Inhibitors (ACEI)
and Angiotensin Receptor Blockers (ARB)
The renin-angiotensin system (RAS) plays a role in the
pathophysiological process of AAA [35]. The molecular
mechanisms involved in AAA formation are elaborated in
several reviews, suggesting that elevation of MCP-1, cy-
clooxygenase-2, osteopontin, oxidative stress and MMPs me-
116 Current Vascular Pharmacology, 2018, Vol. 16, No. 2 Wang et al.

Table 2. Clinical studies on the effect of ACEI and ARB on AAA.

Year No. of Patients Design Follow-up (Years) Effect Reference

2002 438 cohort 4 ACEI did not affect AAA growth rate [147]

2006 15326 case-control NA ACEI prevent AAA rupture [36]

2010 1269 cohort 3.4 ARB decreased AAA growth rate [37]

2010 883 cohort NA ACEI or ARB increased perioperative mortality of AAA repair [42]

2010 1701 cohort 1.9 ACEI enhanced AAA growth [41]

2010 652 cohort 5 ACEI did not relate to AAA growth [148]

2014 122 cohort 0.67 ACEI and ARB attenuated AAA expansion [38]

2015 9441 cohort 5 ACEI and ARB reduced AAA mortality, ACEI reduced risk of surgery [39]

2016 3586 case-control NA ACEI and ARB were not associated with AAA rupture [40]

2016 224 RCT over 2 ACEI did not affect AAA growth rate [43]

No. = number; RCT = randomized controlled trial; NA = not applicable.

diated the effects of Ang II on the aortic wall [12, 35]. A body
of clinical investigations have been accumulated in past 10
years, but their results are divergent (Table 2). A retrospective
case-control study of patients with rupture or intact AAA pre-
sented that ACEI, rather than ARB, effectively reduced risk of
AAA rupture, but the fact that 1% patients received ARB in
this study weakened the conclusion [36]. Nevertheless, a pro-
gram lasting 25 years of surveillance pointed out that ARB
seems to reduce AAA expansion although the effects were not
independent of all confounders [37]. Recently, two observa-
tional investigations validated the role of ACEI and ARB in
inhibition of AAA [38, 39]. One study collected 9441 patients
from nation-wide registries; ACEI and ARB comparably de-
creased mortality, and ACEI users also had a lower risk of
surgery for AAA repair [39]. In contrast, another case-control
follow-up study demonstrated no clear relationship between
RAS blockade and risk of rupture of AAA but lack of smok-
ing information may limit credibility [40]. What is worse,
Sweeting and Railton’s observational trial claimed that the
administration of ACEI increased AAA growth rate and pe-
rioperative mortality [41, 42]. These inconsistencies derived
from different imaging measurements, number of patients,
baseline characteristics and statistical methodology. Recently,
the result of AARDVARK trail, the first randomized trial to
evaluate the effects of ACEI on AAA, was released [43]. 224
patients were randomized to three groups who were treated
with perindopril arginine 10 mg, amlodipine 5 mg or placebo,
respectively and followed more than 2 years. Administration
of perindopril failed to significantly prevent small AAA dila-
tion annually despite the fact that blood pressure was lower in
this group [43]. The number of patients with AAA diameters
that reached 5.5 cm or who underwent surgery were also simi-
lar among these groups. It is suggested that ACEI is not an
effective choice for AAA treatment. Another randomized
clinical trial of ARB is still on-going [44].
2.4. Corticosteroids
Several case reports demonstrated that corticosteroid
therapy was effective for the patients with inflammatory
AAA (IAAA), which is characterized by thickening wall in
aneurysmal portion and fibrous adhesion to adjacent tissue
[45-47]. Corticosteroids mitigated the fibrosis and if there is
no urgency to operate (diameter <5.5 cm), it is the optimal
choice in IAAA [45]. However, until now no guidelines of
medical treatment for IAAA exist. Although an observa-
tional study denied the relationship between corticosteroid
and AAA growth rate, a recent randomized, double-blind,
placebo-controlled clinical trial concluded that preoperative
administration of methylprednisolone facilitated recovery
after endovascular AAA repair [48]. Methylprednisolone 30
mg/kg body weight alleviated the systemic inflammatory
response syndrome (SIRS) from 92-27%, accompanied by
the reduction of interleukin-6 and C-reactive protein [48].
2.5. Anti-platelet Drugs
Intraluminal mural thrombus (ILT) includes inflamma-
tory cells, particularly neutrophils, pro-inflammatory cytoki-
nes and proteolytic enzymes, and plays a central role in AAA
progression and rupture [49]. In a small prospective cohort,
the volume of infrarenal aorta thrombus measured by com-
puted tomography angiography (CTA) in AAA patients was
positively associated with the adverse cardiovascular events
and AAA growth rate [50]. In Ang II-induced AAA models,
anti-platelet drugs significantly diminished AAA formation,
and intriguingly, greatly ameliorated rupture-induced death
in established AAAs [51, 52]. These effects were accompa-
nied by a reduction in macrophage aggregation and MMP
expression [51]. Currently, AAA patients are recommended
to receive low-dose aspirin, but compelling evidence is still
lacking [53, 54]. In agreement with animal experiments,
some observational studies demonstrated that anti-platelet
treatment decelerated medium-sized AAA expansion and
lowered dissection or rupture rate [51, 55]. Conversely, oth-
ers contradicted these views [22, 37, 56]. Predominantly,
Chen’s national retrospective cohort study suggested that
low dose aspirin did not protect AAA patients from mortality
or adverse events after 10-year follow-up [56]. Also, pread-
mission use of low dose aspirin did not change the risk of
Pharmacological Therapy of Abdominal Aortic Aneurysm
AAA rupture in hospital and even worsened 30-day mortal-
ity [57]. Collectively, no high-quality randomized controlled
trials evaluated the importance anti-platelet agents for AAA
patients. A randomized double-blind controlled trial of tica-
grelor, a new anti-platelet drug, is in progress. This trial is
expected to provide evidence about the role of anti-platelet
drugs in AAA [58].
2.6. Mast Cell Stabilizers
Mast cells play vital roles in allergic responses, tumour
and atherosclerosis and studies also emphasized their signifi-
cance in AAA pathogenesis [59]. Mast cell deficiency or its
stabilizers retarded the AAA progression, while activation of
mast cell aggravated AAA growth [60, 61]. The mechanistic
analysis showed that mast cells sparked angiogenesis, SMC
apoptosis, and elevation of MMPs. Proinflammatory factors
including IL-6 and IFN-, chymase, and tryptase mediated
these effects [60, 62]. The abovementioned evidence sug-
gested that mast cell stabilizers, which are extensively used
clinically to combat allergic disease, may also become a
candidate for AAA treatment. Disappointedly, the AORTA
trial, which explored the relationship between mast cell in-
hibitor, pemirolast, and medium-sized AAA expansion, re-
vealed a negative conclusion [63]; 326 patients treated with
10, 25, 40 mg pemirolast or placebo for 1 year had a similar
AAA growth rate. The insufficient dose and study interval
may account for this result. Additionally, medium-sized
AAA, namely 39-49 mm in diameter, is a late stage for ef-
fectiveness of mast cell stabilizers, which can be assessed in
animal models. Varying dosages and long study intervals are
awaited in the future.
3. NEW THERAPEUTIC TARGETS FOR MEDICAL
TREATMENTS OF AAA
3.1. Several Critical Signaling Pathways
Chronic inflammation has long been recognized as a
crucial pathological event in AAAs. NF-B and ets, two
regulators of inflammation, have been reported to be associ-
ated with AAA expansion [64, 65]. In AAA samples ob-
tained from humans, NF-B and ets were observed to be
greatly activated [64, 65]. Perivascular delivery of chimeric
decoy oligodeoxynucleotides (ODNs) efficiently repressed
NF-B and its expression and subsequently slowed AAA
dilation in rat and rabbit models [64, 66]. Predominantly,
ODNs are able to reduce aortic diameter in an established
rabbit AAA model [65]. Exploration of mechanisms sug-
gested inhibition of NF-B and ets significantly decreased
MMPs production and macrophage infiltration, and facili-
tated elastin and collagen synthesis, which was vital to aortic
remodelling [65]. These results suggested that ODNs were
potential therapy for AAA management, but the delivery
method should be further developed
Peroxisome proliferator-activated receptor (PPAR)- is
ubiquitously expressed in all aortic cells including SMCs,
inflammatory cells and fibroblasts. The expression PPAR-
is higher in AAA samples from humans and mice [67]. Ad-
ministration of PPAR- agonists, rosiglitazone or pioglita-
zone, which are used for type 2 diabetes mellitus treatment,
profoundly reduced aortic dilatation and rupture rate accom-
panied by a decline of proinflammatory cytokines and
Current Vascular Pharmacology, 2018, Vol. 16, No. 2 117
macrophage infiltration [68, 69]. Similarly, analysis of
specimens obtained from aneurysmectomy demonstrated that
15 mg/day of PPAR- agonist for >2 months decreased
macrophage infiltration, TNF-
and MMP-9 in the aortic
wall and periaortic fat [70]. The effects of PPAR- agonists
on aorta are pleiotropic (Fig. 1). PPAR- deficiency in SMCs
accelerated AAA development and elastin disintegration,
possibly by increasing cathepsin S [67, 71]. Additionally,
inhibition of PPAR- in aortic adventitial fibroblasts inter-
fered synthesis of elastic fibre components [67]. Also, spe-
cific delivery of PPAR- agonists to macrophage drove
macrophage towards the M2 type, which has anti-
inflammatory effects [72]. These studies suggested PPAR-
agonists potentially restricted AAA progression, but there is
a need for further validation.
The AKT signaling pathway, which can be induced by
growth factors and cytokines, is involved in cellular activi-
ties such as metabolism, proliferation and migration. Phos-
phorylated AKT and total AKT were elevated in both AAA
mouse models and human AAAs. LY294002, an AKT in-
hibitor, attenuated the expansion of AAA [73]. In vitro ex-
periments claimed that macrophages and SMCs treated with
elastase had increased AKT phosphorylation, and MMP9
expression, and these effects were abandoned by the siRNA
against AKT [73]. However, another study indicated that a
lack of AKT2 deteriorated Ang II-induced AAA. The pres-
ence of AKT2 reduced MMP9 and fostered TIMP-1 in hu-
man aortic SMC [74]. Furthermore, fenofibrate inhibited
aortic dilatation and atheroma progression partially because
of up-regulated AKT1 and eNOS [75]. The individual effects
of AKT isoforms are possibly not the same as total AKT.
Different models are also a potential explanation for these
disparities.
Prostaglandin E2 (PGE2) is involved in multiple vascu-
lar inflammatory process including atherosclerosis and AAA,
and EP1-4 receptors mediated its effects [76]. Although EP-
2, -3, -4 are detected in mouse and human AAA tissues, EP-
4 is the only receptor which plays a role in AAA develop-
ment [77]. EP-4 knockout or systemic administration of EP-
4 antagonist strikingly alleviated AAA dilation, and IL-6, IL-
17, MIP-1

MMP-2 and MMP-9 are concomitantly reduced
[78, 79]. Another mechanistic study asserted that EP-4 was
highly expressed in the microvasculature of AAA specimens,
and activation of EP-4 in microvascular endothelial cells
induced angiogenesis in vitro [80]. It has been indicated that
EP-4 was potentially implicated in AAA-related vasculariza-
tion. These stimulating results predicted that EP-4 antagonist
is an alternative target for AAA treatment. The only uncer-
tainty stemmed from Tang’s work that suggested that a lack
of EP-4 in bone marrow-derived cells exacerbated AAA for-
mation [81]. Thus, macrophage specific inhibition of EP-4
may not be a rational choice for therapy.
Notch signaling pathway, which is composed of 4 Notch
receptors 1-4, is highly conserved and ubiquitously ex-
pressed in various species. A series of recent studies linked
Notch signaling to AAA formation, and Notch1 particularly
plays a vital role [82-84]. In AAA patient’s plasma, Notch1
level was increased compared with controls [85]. Further,
Notch1 signaling was also enhanced in Ang II-induced mice
and human AAA tissues, while Doyle reported that Notch1
118 Current Vascular Pharmacology, 2018, Vol. 16, No. 2
6PRRWKPXVFOHFHOOV
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Fig. (1). The pleiotropic effects of PPAR-
agonists on AAA.
was reduced in tissues obtained from human detected by
PCR [82, 84, 86]. It is not clear how this difference occurred.
Using Notch1 haploinsufficiency mice, Hans’ group demon-
strated that Notch1 deficiency reduced AAA progression
[82]. This protective effect may be resulted from regulation
of macrophage polarization, namely, less M1 macrophage
and more M2 macrophage. In parallel, administration of
Notch1 inhibitor also had similar protection against AAA,
implying Notch1 was a potential target for AAA therapy [83,
84]. The clinical use of these inhibitors should be evaluated
in future investigations.
Toll-Like Receptors (TLRs) play pivotal roles in innate
and adaptive immune response, and are also implicated in
AAA development. Knockout of TLR4 reduced AAA dila-
tion in Ang II and CaCl2-induced murine models [87, 88].
Mechanistic studies reported that loss of TLR4 in SMC de-
creased expression of IL-6 and MCP-1, but hardly affected
macrophages [87, 88]. On the other hand, Qin and his co-
workers reported that STAT3 phosphorylation was also a
downstream pathway of activated TLR4, and TLR4 defi-
ciency undermined Ang II-induced STAT3 phosphorylation
[89]. Likewise, inhibitors of TLR4 such as Eritoran and
IAXO-102, effectively diminished AAA development, sug-
gesting TLR4 was a potential target for AAA treatment [89,
90]. In contrast, the role of TLR2 in AAA is still undeter-
mined. Loss of TLR2 hardly influenced AAA pathogenesis,
but Yan’s suggested antagonists of TLR2 strikingly de-
creased AAA, accompanied by the reduction of inflamma-
tory cytokines and MMPs [87, 91]. The involvement of
TLR2 in AAA is complex, and further studies are necessary
to assess therapeutic effects.
3.2. Cell Therapy
Mesenchymal stem cells (MSCs) not only are able to
differentiate into various cell types, but also show potent
anti-inflammatory and immunoregulatory properties [92].
Previously, implantation of bone marrow-derived MSC
(BM-MSC) on aortic adventitia significantly decreased AAA
expansion, and inflammatory cytokines and MMPs were
reduced [93]. To be less invasive, BM-MSCs were injected
Wang et al.
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intravenously via tail vein in Ang II-induced AAA model,
and consistently retarded AAA development [94]. Encourag-
ingly, delivery of MSCs in a catheter-dependent way stabi-
lized and even regressed the formed AAA, similar to clinical
patients [95, 96]. The effects of MSCs on AAA are plei-
otropic, and reduction of MMP-2, MMP-9, IL-6, MCP-1 and
elevation of TIMP-1 may be involved. Notably, Sharma’s
studies demonstrated that MSCs mitigated HMGB1 expres-
sion in nicotinamide adenine dinucleotide phosphate oxidase
(Nox2)-dependent manner in macrophage, and subsequently
inhibited production of IL-17 by CD4+ T cells [97, 98].
Overall, MSCs are promising therapy to alleviate AAA,
though several factors such as delivery method and cell
number need to be further evaluated. Also, the efficacy of
MSCs from different origins such as bone marrow and pla-
centa should be assessed, since these kinds of MSCs are ap-
plied in past studies [93, 98].
Additionally, adoptive transfer of regulatory T cells
(Tregs) and M2 macrophages are reported to effectively al-
leviated AAA development. Intravenous injection of Tregs
significantly reduced AAA expansion in Ang II-induced
AAA model, and concomitantly lowered MMPs and proin-
flammatory cytokines [99, 100]. Conversely, Tregs origi-
nated from IL-10-/- mice failed to inhibit AAA dilation, sug-
gesting that IL-10 mediated the beneficial effects of Tregs
[99, 100]. M2 macrophages, known as anti-inflammatory
phenotype, were transferred into CaCl2-induced AAA model
and dramatically decreased aortic diameter expansion [101].
Tregs and M2 macrophages are two candidates for AAA
treatment.
3.3. Kinases
c-Jun N terminal kinase (c-JNK), one member of mito-
gen-activated protein kinase (MAPK), is also involved in
AAA formation [102, 103]. In Yoshimura’s encouraging
study, phosphorylated c-JNK was greatly increased, which
enhanced MMPs activities and deteriorated tissue repair by
reduction collagen and elastin [15, 102]. In vivo administra-
tion of SP600123, a JNK inhibitor, was observed to not only
limit AAA development, but also lead to regression of estab-
Pharmacological Therapy of Abdominal Aortic Aneurysm
lished AAAs in CaCl2 and Ang II-induced model through
augment of ECM synthesis [102]. In wild type mice treated
with Ang II and nicotine, Guo demonstrated that administra-
tion of SP600123 abrogated AAA formation [104]. These
promising results point to the need for clinical trials.
Another member of MAPKs, extracellular signal-related
kinase (ERK), was enhanced in elastase-induced AAA
model and human samples, reflected by protein level of
phosphorylated ERK [105]. Mice without ERK-1 rarely de-
veloped AAA and MMP2 was predominately reduced in the
meantime, suggesting that ERK-1 possibly regulated MMP2
production [105]. In contrast, analysis of specimens har-
vested from humans elucidated that ruptured AAAs con-
tained high level of MMP2 but low level of ERK-1, chal-
lenging the relationship between ERK and MMP2 [106].
ERK inhibitors can be applied in AAA models in mice in the
future [107].
Protein kinase C-delta (PKC-), a serine/threonine
kinase, has been reported to mediate SMC apoptosis, and
plays a critical role in multiple vascular diseases [108, 109].
Expression of PKC- was dramatically enhanced in AAA
tissues from human and mice [110, 111]. PKC- knockout
mice slowed down AAA dilatation rate with a lower MCP-1
expression in aortic SMC [110]. Perivascular addition of
MCP-1 reversed this effect, suggesting that MCP-1 is a criti-
cal participator involved in PKC delta pathway. A mechanis-
tic study elucidated that PKC- activated NF-B by cytosolic
interacting with subunit p65, and thereby up-regulated MCP-
1 expression in AAA [112]. Unfortunately, PKC- specific
inhibitor is unavailable. Further studies are needed to trans-
late this novel finding into clinical practice.
Receptor-Interacting Protein Kinase 3 (RIP3) is clarified
as crucial mediators of necroptosis, which is a form of well-
regulated necrosis identified in past decades [113]. Recent
progression indicated that RIP3 is involved in aortic SMC
death and contributes to AAA development [114]. In human
AAA tissues and murine elastase-induced model, expression
of RIP3 was significantly elevated at both mRNA and pro-
tein levels [114]. Deprivation of RIP3 was resistant to AAA
dilation, and aortic transplantation suggested that RIP3 in the
aortic wall was responsible for this protective effect. Further
in vitro study elucidated that knockout of RIP3 inhibited
TNF-
-induced SMC necroptosis, and upregulation of RIP3
rendered spontaneous necroptosis. Additionally, silencing
RIP3 reduced the production of several inflammatory cyto-
kines including chemokine (C-C motif) ligand (CCL)-2, IL-
6, TNF-
and VCAM-1, and this pattern was partially de-
pendent on amelioration of p65 phosphorylation and NF-B
activation [114]. This is the first investigation that estab-
lished relationship between necroptosis and AAA, and it is
anticipated that other molecules such as RIP1 may also be
implicated in AAA pathogenesis. Inhibition of RIP3 is an-
other direction for AAA treatment.
3.4. MicroRNA (miRNAs)
MiRNAs are post-transcriptional regulators of gene and
are involved in diverse physiological and pathophysiological
processes. A review comprehensively considered recent pro-
gress of miRNAs and AAA development [115]. MiRNA-21, -
24 and -29b have been validated in experimental animal mod-
Current Vascular Pharmacology, 2018, Vol. 16, No. 2 119
els, but whether these targets can be translated into clinical
practice remains unclear. Systemic injection of agonists or
antagonists inevitably results in severe side effects and local
administration possibly minimized their effects [115].
3.5. Cytokines
Interleukins (IL) are vital mediators of inflammatory
reactions and supposed to be associated with AAA develop-
ment. In human and elastase-induced murine models, IL-1
was significantly elevated, and knockout of IL-1 and IL-1
receptor decreased AAA dilation, concomitantly reduced
macrophage and neutrophil infiltration and maintained
elastin integrity [116]. Anakinra, an antagonist of IL-1 recep-
tor, also disrupted AAA progression in a dose-dependent
manner, suggesting it is a potential treatment for AAA [116].
IL-6 is abundant in AAA tissues, and circulating IL-6 may
function as a biomarker for AAA [117, 118]. Disappoint-
ingly, lack or inhibition of IL-6 declined thoracic aortic an-
eurysms (TAA) expansion rather than AAA formation, chal-
lenging the role of IL-6 in AAA pathogenesis [119]. IL-17,
generated by CD4 + T cells, facilitated AAA inflammation
and was crucial in AAA formation [98]. An in vitro study
revealed that aortic SMC treated with IL-17 increasingly
secreted proinflammatory factors such as IL-6, MCP-1 and
TNF-
[98]. Digoxin and mesenchymal stem cells are two
therapeutic approaches reported to modify the IL-17 pathway
[97, 120]. By far, whether anti-interleukin therapy can be
brought into the clinical scenario is plausible but further in-
vestigations are required.
TNF-
was dramatically elevated in both human serum
and AAA tissues, and Xiong’s study validated the role of
TNF-
in a rodent model [121]. Deficiency of TNF-
inhib-
ited CaCl2-induced AAA, preventing inflammatory cell infil-
tration and MMPs production. Intriguingly, infliximab, a
TNF-
antagonist, was also able to limit AAA expansion,
suggesting infliximab was a candidate for future AAA ther-
apy [121].
3.6. Anti-Oxidative Agents
Excess production of reactive oxygen species (ROS) con-
tinuously damages tissues and plays a vital role in many
chronic diseases including AAA development [122]. Upregu-
lation of ROS leads to aggravation of SMC apoptosis and ele-
vation of MMPs activities. In AAA patients, it has already
been reported that systemic or local oxidative stress drastically
increased [122, 123]. Accumulated evidence indicated that
oxidative stress was a therapeutic target for AAA treatment. In
murine models, elimination of ROS by various anti-oxidative
agents including vitamins, edaravone and a dipeptidyl pepti-
dase (DDP)-4 inhibitor alogliptin limited AAA dilation [124-
126]. However, whether these studies can be translated into
clinical use is still elusive. Supplementation with 50 mg/day
vitamin E for 5.8 years failed to change AAA incidence or
AAA rupture in a controlled, randomized trial, which chal-
lenged the effectiveness of anti-oxidative agents in AAA ther-
apy [127]. More clinical data is needed to verify the function.
3.7. Proteases
It is well established that MMPs disintegrate ECM con-
tents and are involved AAA pathogenesis [128]. Deficiency
120 Current Vascular Pharmacology, 2018, Vol. 16, No. 2
of MMP-2 or MMP-9, secreted by SMC or macrophage re-
spectively, significantly retarded AAA in a CaCl2 induced-
model [129]. Development of MMPs inhibitors, such as
doxycycline abovementioned, is a temptation for future
AAA therapy. However, most clinical trials of MMPs inhibi-
tors failed, possibly due to poor selectivity [130]. Novel
MMP-2 or MMP-9 inhibitors are promising.
Cathepsins are types of lysosomal proteases, and when
activated in acidic environment, they are speculated to poten-
tiate proteolysis and contribute to AAA formation [131,
132]. Accumulated evidence demonstrated that cathepsin C,
K, L, S and G were critical in AAA pathogenesis [133-137].
Lack of cathepsin C diminished AAA expansion, and neu-
trophil infiltration and CXC-chemokine ligand (CXCL) 2
were reduced [133]. Intravenous injection of wild type neu-
trophils reversed CXCL2 generation and AAA formation in
cathepsin C deficiency mice, suggesting that the influence of
cathepsin C on AAA was dependent on neutrophil recruit-
ment [133]. In elastase-induced model, absence of cathepsin
L inhibited AAA development, and in parallel decreased
MCP-1, macrophage and T-cell contents, angiogenesis and
MMPs, but seldom affected SMC apoptosis [136]. The roles
of cathepsin K in distinct murine models are still disputable
[134, 138]. In an Ang II-induced AAA model, apoE-/-
cathepsin K-/- knockout did not protect from AAA severity;
compensatory activation of other proteases may account for
this negative result [138]. Subsequently, Sun contradicted
that cathepsin K deficiency decreased AAA formation, ac-
companied by reduction of CD4+ T-cell aggregation and
SMC apoptosis [134]. Their study explained that infusion of
Ang II changed peripheral inflammatory cell phenotypes,
which obscured the function of cathepsin K in AAA. Simi-
larly, cathepsin G interfered CaCl2-induced AAA develop-
ment, but hardly affected an Ang II-induced AAA murine
model [137]. These investigations suggested complicated
mechanisms involved in the cathepsin family in AAA expan-
sion. Deprivation of cathepsin S significantly inhibited AAA
formation and reduced SMC apoptosis and monocyte and T-
cell infiltration [135]. Promisingly, recent discovery of
cathepsin S inhibitor, LY3000328, was found to greatly re-
duce CaCl2-induced AAA [139]. Potent, highly selective
inhibitors of cathepsin family represent a tempting future for
AAA treatment.
3.8. Others
Urocortin (UCN) is a member of corticotropin-releasing
hormone family and also a crucial regulator of cardiovascu-
lar systems [12]. Rush’s genome expression analysis of tis-
sues from Ang II-induced AAA model suggested that UCN3
expression was diminished in suprarenal part of aorta, which
is vulnerable to AAA formation [140]. This study for the
first time established the relationship between UCN and
AAA. Subsequently, their group detected UCN and its recep-
tors, and found that expression of UCN2 and corticotrophin
releasing factor receptor 2(CRFR2) was significantly higher
in the AAA body compared with AAA neck [141]. Immuno-
histochemical staining revealed that UCN2 expression over-
lapped with T lymphocyte and neutrophil rich areas, suggest-
ing that these inflammatory cells were a putative source of
UCN2 [141]. Likewise, plasma UCN2 levels in AAA pa-
tients were also elevated. In vitro, UCN2 was able to inhibit
Wang et al.
SMC proliferation by evoking G1 cell cycle arrest, which
was mediated by AKT phosphorylation [141]. Unfortunately,
until now, the effect of UCN2 on AAA pathogenesis has not
been evaluated directly in UCN2 deficiency mice. Further in
vivo studies will supply more information about the role of
UCN2 in AAA formation.
It has been observed that glucose metabolism was en-
hanced in AAA patients measured by 18F-FDG uptake,
which is correlated with the up-regulation of glucose trans-
porters [142]. To verify the role of glycolysis in AAA dila-
tion, Tsuruda and co-workers showed that glycolysis inhibi-
tor, 2-deoxyglucose, significantly attenuated the AAA for-
mation in CaCl2- and Ang II-induced mice models. Subse-
quent investigations of mechanisms revealed that 2-
deoxyglucose decreased expression of MCP-1, IL-1, and
IL-6 in monocytes as well as the adherent ability of mono-
cytes to vascular endothelial cells [142]. Their study pro-
vided a potential novel therapeutic target. However, this
needs to be further validated in the future.
SMC phenotypic switching, featured by repressing SMC
markers and elevation of MMPs, occurs in early AAA for-
mation [143]. KLF4 was speculated to modulate SMC phe-
notype, and its function in AAA was affirmed by Salmon’s
group [144]. KLF4 was greatly upregulated in experimental
and human AAA, and the expression was co-localised with
SMCs [144]. They created SMC-specific KLF4 knockout
mice and deciphered that KLF4 deficiency ameliorated AAA
expansion by interacting with SMCs. Therefore, KLF4 may
be a potential target for AAA management. However,
whether administration of KLF4 inhibitor systemically will
interfere activities of different cell types is obscure.
TSP-1 is a pleiotropic ECM protein, which regulates a
body of biological activities including cell migration and
angiogenesis. Recent studies correlated TSP-1 with AAA
pathogenesis, but the conclusion seems conflicting [145,
146]. TSP-1 was upregulated, evidently in adventitia, in hu-
man AAA specimens and experimental murine models
[145]. Knockout of TSP-1 limited AAA dilation in both elas-
tase and CaPO4-induced models, accompanied by the reduc-
tion of macrophage aggregation and inflammatory cytokines.
Further mechanistic experiments elaborated that deficiency
of TSP-1 perturbed adhesive and migratory abilities of
monocytes, which accounted for the protective effects [145].
Nevertheless, Krishna et al. reported that injection of LSKL,
a peptide antagonist of TSP-1, deteriorated the already-
formed AAA in an Ang II-induced model [146]. In the
meantime, administration of LSKL hampered the TGF-1
pathway, characterized by low TGF-1 and phosphorylated
smad2/3 levels and expressions of TGF- receptors [146].
Their work provided novel mechanism TSP-1 involved in
AAA formation, and practical delivery of TSP-1 modulators.
The role of TSP-1 in AAA is still elusive, and whether TSP-
1 can be regarded as a treatment target needs to be evaluated.
CONCLUSION
We reviewed current medical treatments for AAA, and
there are no favourable and definitive conclusion supporting
one or several classes of pharmacological agents. Most of the
existing evidence is from retrospective and observational
studies, and the outcomes are conflicting. Several large, ran-
Pharmacological Therapy of Abdominal Aortic Aneurysm
domized, placebo-controlled, double-blind trials are in pro-
gress, and it is anticipated that future recommendations de-
rived from these trials can better guide clinical practice.
Though mechanisms of AAA formation are not fully elabo-
rated, previous studies unravelled several dominant media-
tors and signaling pathways in AAA development, and these
may become molecular targets for AAA control. Fascinat-
ingly, interference of some pathways such as c-JNK even
leads to remission of AAA. Their agonists or antagonists are
promising candidates for a pharmacological approach, but
the safety, dosage, delivery and side effects should be vali-
dated in future studies. The advancements of pharmacologi-
cal therapy may switch a surgical disease into a medical dis-
ease.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science
Foundation of China [81470384, 81270179].
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