Abstract
Atherosclerosis (AS) is a major cause of cardiovascular diseases such as coronary heart disease, heart failure and stroke. Abnormal lipid metabolism, oxidative stress and inflammation are the main features of AS. Ferroptosis is an iron-driven programmed cell death characterized by lipid peroxidation, which have been proved to participate in the development and progression of AS by different signal pathways. NRF2-Keap1 pathway decreases ferroptosis associated with AS by maintaining cellular iron homeostasis, increasing the production glutathione, GPX4 and NADPH. The p53 plays different roles in ferroptosis at different stages of AS in a transcription-dependent and transcription- independent manner. The Hippo pathway is involved in progression of AS, which has been proved the activation of ferroptosis. Other transcription factors, such as ATF3, ATF4, STAT3, also involved in the occurrence of ferroptosis and AS. Certain proteins or enzymes also have a regulatory role in AS and ferroptosis. In this paper, we review the mechanism of ferroptosis and its important role in AS in an attempt to find a new relationship between ferroptosis and AS and provide new ideas for the future treatment of AS.
Highlights
The main lesion of AS is lipid deposition in the arterial wall, accompanied by proliferation of smooth muscle cells and fibrous matrix, which gradually forms atherosclerotic plaques (Zhu et al, 2018)
Ferroptosis related with cell density in epithelial cells was mediated by E-calmodulinmediated cell-cell contact, which activates Hippo signaling via the NF2 tumor suppressor protein, thereby inhibiting the activity of the nuclear translocation and transcriptional co-regulator YAP, which can target including acyl-CoA synthetase long chain family member 4 (ACSL4) and Trans-ferrin Receptor 1 (TFR1) to promote ferroptosis (Wu et al, 2019a)
The development of ferroptosis is associated with restricted GSH synthesis, disturbances in iron homeostasis, accumulation of lipid peroxides and fatty acid synthesis, which are closely linked to the development of AS
Summary
The main lesion of AS is lipid deposition in the arterial wall, accompanied by proliferation of smooth muscle cells and fibrous matrix, which gradually forms atherosclerotic plaques (Zhu et al, 2018). Ferroptosis is a regulated cell death dependent on reactive oxygen species (ROS) production and iron overload (Wang et al, 2020a). The basic mechanism of ferroptosis is the interaction of intracellular free iron with hydrogen peroxide via the Fenton reaction, leading to the depletion of plasma membrane polyunsaturated fatty acids (PUFAs) (Stockwell et al, 2017). Ferroptosis is regulated by a variety of cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and the metabolism of amino acids, lipids and sugars. Fe2+ in LIP promote ferroptosis by Fenton reaction.
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