Cigarette tar mediates macrophage ferroptosis in atherosclerosis through the hepcidin/FPN/SLC7A11 signaling pathway

Cigarette smoking, a major risk factor for cardiovascular diseases (CVD), has been shown to aggravate the progression of atherosclerosis (AS) [1,2]. There is strong evidence that smoking accelerates the formation of vulnerable plaque containing massive necrotic core [3]. Our previous study based on 465 AS plaques showed that the incidence of lipid plaque and thin-cap fibroatheroma in smoking patients was significantly higher than that in non-smoking patients [4]. Smoking has been reported to increasing the production of reactive oxygen species (ROS) and proinflammatory cytokines, resulting in vascular damage and inflammatory cells infiltration [5]. In addition, Smoking promotes foam cell formation by affecting the cholesterol efflux function of macrophages [6].

Cigarette smoke is a complex noxious substance of numerous chemicals with carcinogenic, mutagenic, and cytotoxic potential. However, previous studies of smoking on AS mainly focused on nicotine [7]. The specific effects of tar, the main toxic substance in smoke, on AS have not been elucidated. A meta-analysis based on 16 clinical studies indicated that the risk in the lower tar smokers is estimated to be decreased by 14% for heart disease than that in the higher tar smokers [8]. Cigarette tar contains high amount of aromatic hydrocarbons, nitrogen oxides, phenols, heavy metals, and free radicals. Despite the lack of reports on the role and mechanism of tar in AS progression, its main components have been confirmed to pass through the circulation to impair the vascular beds and affect the whole/local immune-inflammatory state. In vitro studies on aromatic hydrocarbons have pointed out the benzo[a]pyrene participate in the activation of inflammation through aryl hydrocarbon receptor (AHR) in vascular endothelial cells [9]. Free radicals represented by hydroquinone and aniline were verified to strongly induce cell death through the caspase 9/3-dependent pathway and RIPK1/ROS pathway, respectively [10,11].Numerous studies have shown that the most abundant dead cells in AS plaque are macrophages [12]. The death of macrophages directly leads to the enlargement of the necrotic core, which subsequently causes intraplaque inflammation and collagen fibril degradation, further increasing plaque vulnerability [13]. Apoptosis has been reported to be the key mechanism of macrophage death in AS. However, with the deepening of research in recent years, the definition of programmed cell death (PCD) has been expanded [14]. Ferroptosis is a new form of PCD caused by iron-dependent lipid peroxidation. Intracellular iron overload mediated by hepcidin, ferroportin (FPN) and TFR1 would generate lipid ROS through fenton reaction to damage the cell membrane [15]. Ferroptosis occurs when the antioxidant system represented by SLC7A11, glutathione (GSH) and GPX4 is unable to remove excessive lipid ROS [16]. Although iron overload has been found to happen in macrophages at the necrotic core [17], no information is available on macrophage ferroptosis in the development of AS.

Hepcidin is a central regulator of iron homeostasis in macrophages, whose function is achieved by binding to FPN, the only mammalian non-heme iron export protein in the body [18]. Disturbances in the regulation of hepcidin expression are associated with various blood diseases, such as hereditary hemochromatosis, anemia of inflammation and beta thalassemia syndrome [19]. Of note, hepcidin has been found to involved in the pathological process of AS. Recent studies have shown that high levels of serum hepcidin are highly associated with vascular injury and arteriosclerosis progression [20,21]. An experimental study demonstrated that activated hepcidin promoted iron overload in macrophages within the plaque and induced cellular cholesterol disequilibrium and foam cell formation [22].

In this study, we proved cigarette tar exacerbates atherogenesis through promoting lipid peroxidation and ferroptosis in macrophages. By constructing hepcidin deficiency and SLC7A11 overexpression mice models, we clarified the molecular mechanism underlying tar-induced macrophage ferroptosis. In addition, we confirmed the possible mechanism of tar in regulation of hepcidin based on NF-κB pathways.

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