Abstract
Atheroclerosis refers to a chronic inflammatory disease featured by the accumulation of fibrofatty lesions in the intima of arteries. Cardiovasular events associated with atherosclerosis remain the major causes of mortality worldwide. Recent studies have indicated that ferroptosis, a novel programmed cell death, might participate in the process of atherosclerosis. However, the ferroptosis landscape is still not clear. In this study, 59 genes associated with ferroptosis were ultimately identified in atherosclerosis in the intima. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for functional annotation. Through the construction of protein–protein interaction (PPI) network, five hub genes (TP53, MAPK1, STAT3, HMOX1, and PTGS2) were then validated histologically. The competing endogenous RNA (ceRNA) network of hub genes was ultimately constructed to explore the regulatory mechanism between lncRNAs, miRNAs, and hub genes. The findings provide more insights into the ferroptosis landscape and, potentially, the therapeutic targets of atherosclerosis.
Highlights
Coronary artery disease (CAD) and stroke, caused by atherosclerosis (AS), are considered as types of chronic inflammatory arterial diseases characterized by the accumulation of lipids and the formation of atherosclerotic plaques (Benjamin et al, 2017; Libby et al, 2019)
To investigate FRGs differentially expressed in atherosclerotic plaques, 149 FRGs were extracted from FerrDb, a database for regulators, markers, and diseases associated with ferroptosis
The Toll-like receptor pathway, NOD-like receptor pathway, transforming growth factor beta (TGF-β) signal pathway, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signal pathway, cell cycle, vascular smooth muscle contraction, and cytosolic DNA sensing pathway were significantly enriched in atherosclerotic plaques (Figure 2)
Summary
Coronary artery disease (CAD) and stroke, caused by atherosclerosis (AS), are considered as types of chronic inflammatory arterial diseases characterized by the accumulation of lipids and the formation of atherosclerotic plaques (Benjamin et al, 2017; Libby et al, 2019). Endothelial dysfunction and lowdensity lipoprotein cholesterol (LDL) infiltration into the subendothelial layer of arteries initiated atherogenesis (Peluso et al, 2012; Förstermann et al, 2017; Kattoor et al, 2017). Ferroptosis is a form of programmed cell death definitely modulated by iron-dependent lethal lipid peroxidation. Iron overload or the inactivation of glutathione peroxidase 4 (GPX4) promoted reactive oxygen species (ROS), which hastened lipid peroxidation, eventually leading to ferroptosis (Tang et al, 2021). ROS was implicated in endothelial dysfunction, which was the initiating link of AS (Maiocchi et al, 2021). Recent studies have elucidated the status of ferroptosis in AS
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