Low shear stress promotes atherosclerosis by inducing endothelial ferroptosis via the P53/xCT pathway

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Background Atherosclerotic lesions commonly develop in curved or bifurcated arteries, where blood flow exhibits characteristics of low shear stress (LSS). Subjected to LSS continually, endothelial cells (ECs) adopt a pro-atherosclerotic phenotype. Ferroptosis is a recently identified form of controlled cell demise prompted by iron-dependent buildup of cellular reactive oxygen species (ROS), which has been associated with diverse cardiovascular diseases, particularly atherosclerosis (AS). P53 is a broadly acting tumor suppressor that can be activated by diverse stimuli and mediates multiple biological outcomes, including cell cycle arrest, DNA repair, apoptosis, and ferroptosis. However, it remains unknown whether LSS promotes the development of AS by inducing P53-dependent ferroptosis in endothelial cells. Methods In our experiments, we induced LSS by partial ligation of the right common carotid artery in high-fat diet-fed (HFD) male ApoE -/- mice. The application of LSS applied on human umbilical vein endothelial cells (HUVECs) in vitro was through a parallel plate flow chamber configuration. Results Our findings demonstrated that LSS induced endothelial ferroptosis, which in turn accelerated AS development both in vivo and in vitro. This effect was partially counteracted by both the ferroptosis inhibitor Fer-1 and endothelium-specific glutathione peroxidase 4 (GPX4) overexpression in ApoE -/- mice. Mechanistically, LSS was found to promote ferroptosis by driving the upregulation and nuclear translocation of P53 in HUVECs, which transcriptionally repressed xCT. Conversely, silencing or inhibiting P53 mitigated LSS-induced ferroptosis. These findings were corroborated in vivo, where endothelial-specific P53 knockout or inhibition effectively suppressed atherosclerotic plaque formation in mice. Conclusions Our experiments suggested that LSS promotes atherosclerosis by inducing endothelial ferroptosis through the P53/xCT signaling pathway.

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