Ferroptosis: the potential value target in atherosclerosis

Abstract

In advanced atherosclerosis (AS), defective function-induced cell death leads to the formation of the characteristic necrotic core and vulnerable plaque. The forms and mechanisms of cell death in AS have recently been elucidated. Among them, ferroptosis, an iron-dependent form of necrosis that is characterized by oxidative damage to phospholipids, promotes AS by accelerating endothelial dysfunction in lipid peroxidation. Moreover, disordered intracellular iron causes damage to macrophages, vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and affects many risk factors or pathologic processes of AS such as disturbances in lipid peroxidation, oxidative stress, inflammation, and dyslipidemia. However, the mechanisms through which ferroptosis initiates the development and progression of AS have not been established. This review explains the possible correlations between AS and ferroptosis, and provides a reliable theoretical basis for future studies on its mechanism.

Ferroptosis Signaling and Regulators in Atherosclerosis

“…Depletion of the antioxidant GSH or ox-LDL lead to the accumulation of intracellular lipid peroxide ( Dixon et al, 2012 ; Kattoor et al, 2017 ; Ouyang et al, 2021 ). Over-expression of GPX4 in ApoE −/− mice attenuates the upregulation of endothelial cell adhesion molecule and monocyte-endothelial cell adhesion, thereby inhibiting the development of AS ( Guo et al, 2008 ).…”

“…12/15-LOX promotes increased trans-endothelial transport of ox-LDL and deposition of ox-LDL in the sub-endothelial space ( Li et al, 2018 ). ALOX12 exhibits higher methylation levels in atherosclerotic plaques, particularly in endothelial cells, which is essential for p53-mediated ferroptosis following stress ( Ouyang et al, 2021 ). The p53 gene also promotes ferroptosis through histone modification with non-dependent of p53 ( Dai et al, 2020 ).…”

“…In addition, excess iron activates ROS production and induces lipid peroxidation in macrophage-derived foam cells, leading to instability of atherosclerotic plaques. Disturbed iron metabolism in macrophages is involved in the inflammatory response that exacerbates the severity of AS, and iron overload also closely related to the induction of macrophage polarization towards the inflammatory phenotype M1 via the ROS/acetyl-p53 pathway ( Zhou et al, 2018 ; Handa et al, 2019 ; Ouyang et al, 2021 ).…”

“…In addition, endoplasmic reticulum stress promotes intracellular H 2 O 2 levels by upregulating ATF3 and enhances intracellular Fe 2+ by upregulating the expression of the transferritin receptor, leading to the accumulation of toxic lipid peroxides in cells. whether the high expression of ATF3 in AS is associated with ferroptosis needs to be further explored ( Ouyang et al, 2021 ).…”

Ferroptosis: New Dawn for Overcoming the Cardio-Cerebrovascular Diseases

“…It has been reported that when ferroptosis occurs in neurons, then microglia are activated and release toxic substances including pro-inflammatory factor IL-6, which can cause neuro-inflammation and lead to further brain damage ( Tang et al, 2020 ). In addition, ferroptosis also changes the inflammatory phenotype in macrophages ( Ouyang et al, 2021 ), which promotes macrophage polarization and then aggravates inflammation ( Yu et al, 2021 ). Ferroptosis is capable of directly releasing the pro-inflammatory damaged-associated molecular patterns (DAMPs) that promote the development of inflammation and numerous inflammatory diseases.…”