Abstract P346: Ferroptosis Is Critical In Diabetic Atherosclerosis Through Heme Oxygenase 1 Regulated Lipid Peroxidation Pathway

Introduction: The patients with diabetes dramatically accelerates atherosclerosis. Although improved diabetes treatment strategy has prevented the pathogenesis, diabetic atherosclerosis is still the main cause of morbidity and mortality. It is urgent to clarify its in-depth mechanism and identify new therapeutic targets for preventing diabetic atherosclerosis. Hypothesis: We assessed the hypothesis that ferroptosis and HMOX1 may be implicated in diabetes atherosclerosis through comprehensive in-depth bioinformatics analysis. Methods and Results: Analysis of Gene expression profiles (GSE30169 and GSE6584) provided a total of 91 differentially expressed genes (DEGs) including 68 up-regulated and 23 down-regulated genes (A). Ferroptosis, a type of programmed cell death dependent on iron, and HMOX1, a gene that encodes heme oxygenase, were identified as key factors in diabetes atherosclerosis (B). To explore the potential mechanism, we measured iron content and reactive oxygen species (ROS) generation and conducted a lipid peroxidation assay. Compared with animals on a normal diet (ND), ferroptosis and HMOX1 expression in ApoE -/- mice on high-fat diet (HFD) were significantly increased (C, n = 3). Ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively attenuated the diabetic atherosclerosis area in HFD animals (D, n = 5, P < 0.01 vs HFD). In addition, Fer-1 restored the ferroptosis-related protein (GPX4 and SLC7A11) with high glucose high lipid (HGHL) treatment in Mouse arterial endothelial cells (MAECs) (E, n=6). More importantly, HMOX1 deficiency rebalanced Fe 2+ overload, decreased iron content, reduced ROS, and alleviated the lipid peroxidation, which led to the reduction of ferroptosis in diabetic endothelial cells (F). Conclusions: We demonstrate that ferroptosis is critical in diabetic AS progression and HMOX1 is an implicated factor responsible for ferroptosis in diabetic AS development, suggesting HMOX1 may serve as a potential therapeutic or drug development target.