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.