Potential intervention target of atherosclerosis: Ferroptosis (Review)

Abstract

Atherosclerosis (AS) is a chronic inflammatory disease of the blood vessels, which is mainly characterized by the form of atherosclerotic plaques and vascular endothelial injury. Its formation involves abnormal lipid metabolism, oxidative stress and inflammation, as well as other processes. AS is the direct cause of various acute cardiovascular and cerebrovascular diseases, such as acute myocardial infarction and acute ischemic stroke. Early intervention in the atherosclerotic inflammatory process and lesion progression is beneficial, and has been associated with the primary prevention of a range of related diseases. Ferroptosis is a non‑apoptotic form of cell death different from cell necrosis and autophagy, which has been shown to participate in atherogenesis and atherosclerotic progression through numerous signaling pathways. The main characteristic of ferroptosis is the formation of high levels of cellular iron catalytic free radicals, unsaturated fatty acid accumulation and iron‑induced lipid reactive oxygen species accumulation, which can cause oxidative stress, and subsequent DNA, protein and lipid damage. There are numerous hypotheses about the pathogenesis of AS. At present, it has been suggested that ferroptosis can accelerate the progression of AS and that inflammation is associated with the whole process of AS. The mechanisms and signaling pathways related to the involvement of neuroinflammation and ferroptosis in the progression of AS, and therapeutic targets associated with ferroptosis have not yet been elucidated. The present review article evaluated the involvement of ferroptosis in the progression of AS from the perspectives of ferroptotic cell death, the pathogenesis of AS and nervous system inflammation, with the aim of exploring new therapeutic targets for AS.

Keywords: atherosclerosis; ferroptosis; inflammation; ischemic stroke.

Figure 1.

Molecular mechanisms of ferroptosis. Extracellular Fe³⁺ is transported to the cells byTfR1. The Fe³⁺ is reduced to Fe²⁺ to play a role in mitochondria or for storage in the form of ferritin, and the remainder is exported from the cell through ferroportin to maintain iron homeostasis. The reaction of PUFAs and excess reactive oxygen species, which occurs on the cell membrane, is catalyzed by ACSL4 and LPCAT3, and mediated by ALOX, which leads to lipid peroxidation. GPX4 can reduce ferroptosis by inhibiting lipid peroxidation. PUFAs, n-3 polyunsaturated fatty acids; ACSL4, acyl-CoA synthetase long chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; ALOX, arachidonate lipoxygenase; PL, phospholipid; GPX4, glutathione peroxidase 4; NCOA4, nuclear receptor coactivator 4; TfR1, transferrin receptor 1.

Figure 2.

Ferroptosis and atherosclerosis. Intracellular free iron generates hydroxyl radicals through the Fenton reaction and participates in the synthesis of lipoxygenase to generate lipid peroxides. System x_c⁻ functions as a cystine/glutamate transporter that imports a cystine molecule in exchange for an intracellular glutamate molecule. Cystine is converted to GSH through a series of reactions and GPX4 suppresses ferroptosis by reducing lipid peroxides to their lipid alcohol forms using GSH. When this process is inhibited, ferroptosis occurs, resulting in the release of DAMPs, the expression of pro-inflammatory factors and inflammation, which ultimately lead to the formation and exacerbation of atherosclerosis. GSH, glutathione; GPX4, GSH peroxidase 4; DAMPs, danger-associated molecular patterns; GSSG, oxidized glutathione.

Figure 3.

Ferroptosis is triggered by excessive lipid peroxidation. ox-LDL induces iron accumulation. Free iron has strong endothelial cytotoxicity and, at the same time, lipid-laden macrophages accumulate in the arterial subendothelial space, which promotes the inflammatory response of the arterial wall. Iron deposition in plaques causes ox-LDL to activate the TLR4/NF-κB signaling pathway and promotes foam cell formation. Ferric iron retention in atherosclerotic plaques promotes oxidative stress, lipid peroxidation and increases the instability of plaque. The occurrence of ferroptosis is involved in numerous processes of atherosclerosis. Lipid peroxidation, plaque hemorrhage and iron deposition are important characteristics of advanced atherosclerotic plaques. LDL, low-density lipoprotein; ox-LDL, oxidized LDL; MMPs, matrix metalloproteases; CRP, C-reactive protein; SMC, smooth muscle cell.