Work

SQSTM1 upregulation-induced iron overload triggers endothelial ferroptosis in nicotine-exacerbated atherosclerosis

Year: 2024

Type: article

Abstract: AIMS: Nicotine-exacerbated atherosclerosis significantly increases global mortality. Endothelial cells, which line the interior of blood vessels, are crucial for maintaining vascular function. How nicotine is involved in vascular remodeling in atherosclerosis via modulating endothelial dysfunction remains unknown. MATERIALS AND METHODS: Comprehensive gene expression analyses identified key genes upregulated in the ferroptosis pathway in smoking-exacerbated atherosclerosis. Predictive models integrating these ferroptosis-related genes were constructed to differentiate atherosclerotic plaques. KEY FINDINGS: Here, we reveal that ferroptosis mediates nicotine-induced endothelial dysfunction, exacerbating atherosclerosis. Mechanistically, nicotine elevates sequestosome 1 (SQSTM1), leading to iron overload and an increase in reactive oxygen species (ROS) and the levels of ferroptosis markers heme-oxygenase 1 (HMOX1) and prostaglandin-endoperoxide synthase 2 (PTGS2), contributing to ferroptosis in endothelial cells and the aberrant production of inflammatory factors. Pharmacological inhibition of ferroptosis and normalization of iron levels by knocking down SQSTM1 mitigate endothelial ferroptosis and reduce production of pro-inflammatory factors. Diagnostically, human plasma levels of HMOX1, SQSTM1, and PTGS2 are elevated in smokers with atherosclerosis but reduce in ex-smokers. Predictive models, including a support vector machine integrating these ferroptosis-related genes, effectively differentiate between early- and advanced-stage atherosclerotic plaques. SIGNIFICANCE: SQSTM1 upregulation-induced iron overload triggers endothelial ferroptosis in nicotine-exacerbated atherosclerosis, suggesting excellent predictive efficacy for atherosclerosis development and potential for clinical applications. TRIAL REGISTRATION: This study has been registered in the Chinese Clinical Trial Registry (ChiCTR2400083484, Registration Date: April 26, 2024).

Source: Life Sciences

DOI: 10.1016/j.lfs.2024.123330