Introduction
Atherosclerosis and associated acute coronary syndrome are leading
causes of morbidity and mortality worldwide
(Herrington et al. , 2016). Despite
its complex aetiology,
atherosclerosis is considered a progressive inflammatory disease caused
by abnormal lipid metabolism in which macrophages play a central role by
inducing inflammatory responses and foam cell formation
(Seneviratne et al. , 2017).
Oxidised low-density lipoprotein
(ox-LDL) plays an important role in the formation of atherosclerotic
plaques and is internalised by surface scavenger receptors, mainly, CD36
(Nicholson et al. , 2001). Notably,
Toll-like receptor 4 (TLR4) and CD36 can respond to ox-LDL, thereby
triggering an intracellular signalling cascade that leads to the
activation of the downstream factors MyD88 and NF-κB
(Chen et al. , 2017). NF-κB
activation is responsible for the pro-inflammatory effects of
angiotensin II (Ang II) in the blood vessel wall; it activates the
production of the pro-inflammatory cytokine IL-6. IL-6 is an important
pathogenic factor of atherosclerosis; it interacts with the
renin-angiotensin system (Wassmannet al. , 2004) (5).
The atherogenic effect of macrophage inflammasomes, mainly, NLRP3 (NLR
Family Pyrin Domain Containing 3), is also being extensively
investigated (Hoseini et al. ,
2018; Tang et al. , 2018).
Activated NLRP3 recruits caspase-1, thereby converting the inflammatory
factor IL-1β into its mature form, ultimately leading to pyroptosis.
IL-1β is a potent atherogenic cytokine that promotes the secretion of
many other cytokines and chemokines
(Seneviratne et al. , 2017).
Further, IL-1β induces the expression of adhesion molecules,
endothelin-1, and inducible nitric oxide synthase in endothelial cells.
The nuclear translocation of p65 promotes pro-IL1β transcription
(Kauser et al. , 1998). In
addition, Western diet-fed Ldlr-/-mice transplanted
with bone marrow cells lacking NLRP3 showed reduced lesion size, along
with reduced IL-1 and IL-18 levels (Duewellet al. , 2010).
Currently, statins are the most effective treatment for lowering
lipoprotein levels and preventing major cardiovascular events. However,
statins have shown severe withdrawal responses in clinical trials. For
example, in patients with hypercholesterolemia, atorvastatin withdrawal
rapidly increased the activation of pro-inflammatory and thrombogenic
pathways (Güleç Başer et al. ,
2018), while acute simvastatin withdrawal after myocardial infarction
was associated with an increased rebound in the CRP (C-reactive protein)
levels (Babu et al. , 2011).
Therefore, it is necessary to develop a safer and more effective method
for protection against vascular inflammation. Arsenic-based compounds
have been used to treat diseases for more than 2,000 years. Among such
compounds, arsenic trioxide
(As2O3,
ATO) has garnered attention due to its therapeutic activity. In the past
two decades, the therapeutic efficacy of ATO against acute promyelocytic
leukaemia (APL) has been approved by US Food and Drug Administration
(FDA) (Au et al. , 2003;
Zhao et al. , 2021). Moreover, ATO
has also shown efficacy against other diseases, such as multiple myeloma
(Munshi, 2001), and various solid tumours
(Subbarayan et al. , 2014) due to
its anti-proliferative properties. Although ATO use is limited by its
toxicity, its combination with nanotechnological strategies could
increase its bioavailability while reducing systemic toxicity, as has
been observed with various conventional chemotherapy drugs
(Akhtar et al. , 2017). Many
researches showed ATO-eluting stents inhibited in-stent restenosis at
the responding concentration of ATO (Zhanget al. , 2017). Mechanistically, ATO exerts anti-tumour effects
by inhibiting the secretion of various pro-inflammatory cytokines and
NF-κB transcription (Zhang et al. ,
2016). Nevertheless, the atheroprotective role of ATO in
atherosclerosis, especially, in macrophages, is largely unknown.
In this study, we investigated the potential atheroprotective nature of
ATO in atherosclerosis and the mechanism
whereby it disturbs macrophage lipid
metabolism and inflammatory responses.