Ferroptosis Signaling and Regulators in Atherosclerosis

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.

Keywords: Hippo; Nrf2; atherosclerosis; ferroptosis; p53.

FIGURE 1

Mechanism of ferroptosis occurrence. AA/AdA is activated by ACSL4 to become AA/AdA-CoA, then AA/AdA-CoA is esterified by LPCAT3 to AA/AdA-PE, AA/AdA-PE generates PLOOH through the Fenton reaction and the enzymatic reaction of ALOX15. Systemic Xc- promotes the synthesis of GSH, which together with GPX4 converts PLOOH to PLOH. Extracellular TF binds to Fe³⁺ and translocated into the cell via TFR1. The cell contains Fe3+, TF and TFR1 into the endosome by endocytosis. STEAP3 reduces Fe³⁺ to Fe²⁺, which is transported to the cytoplasm via DMT1 to form LIP. Fe²⁺ in LIP promote ferroptosis by Fenton reaction. Ferritin reduces Fe²⁺ is decreased by storing of Ferritin and the excrete via FPN. Ferritin also binds to NCOA4 to release Fe²⁺ via ferritinphagy.

FIGURE 2

NRF2 is involved in the regulation of ferroptosis. Under normal conditions, NRF2 is degraded by the Keap1-CUL3-RBX1 E3 ubiquitin ligase complex-targeted proteasome. Under oxidative stress conditions, NRF2 is no longer degraded, thus allowing nuclear translocation and binding to the ARE. NRF2 promotes G6PD expression to increases NADPH via the pentose phosphate pathway, GSH and TXN production is dependent on NADPH, which promotes CoQ10 production. NRF2 promotes the expression of SLC7A11, GCLC, GCLM, GSS to increase GSH synthesis, and NRF2 also promotes the expression of GPX4. GPX4 converts GSH to GSSG to reduce lipid hydrogen peroxide. NRF2 can promote the expression of ferritin and FPN to store Fe²⁺ and excrete Fe²⁺ respectively, and reduce Fe²⁺ in LIP; Nrf2 also promote the expression of HO-1.

FIGURE 3

The p53 and Hippo pathways regulate ferroptosis. p53 promotes the expression of ALOX15 in a transcription-dependent manner to promote ferroptosis, and ALOX15 can contribute to the development of AS. p53 regulates ferroptosis by inhibiting GSH through SLC7A11 and promoting GSH production through p21. In contrast, GSH can inhibit the development of AS. When the Hippo signaling pathway is opened, MST1/2 phosphorylates MOB1 and LATS1/2 and increases the interaction between them. Phosphorylated YAP/TAZ by LATS1/2 is degraded in the cytoplasm with the assistance of SAV1. When the Hippo signaling pathway is closed, the level of YAP phosphorylation decreases and translocates into the nucleus where it binds to the transcription factor TEAD to produce ACSL4, which promotes intracellular lipid peroxidation. TFR1, which increases intracellular Fe²⁺ concentration, and NOX4 and NOX2, induce intracellular ROS production and development of ferroptosis.