Abstract 521: Pharmacologic Inhibition Of Ferroptosis Attenuates Abdominal Aortic Aneurysm Formation

Abstract

Background: Abdominal aortic aneurysms (AAA) are characterized by thrombus formation, aortic inflammation, and vascular remodeling. This study investigates the role of ferroptosis, an iron-dependent non-apoptotic cell death pathway, and its pharmacologic inhibition in the pathogenesis of AAA formation. Methods: AAAs were induced in 8- to 12-week old male C57BL/6 mice using topical 0.4 U/ml type 1 porcine pancreatic elastase treatment, or deactivated elastase as control. Mice in the elastase group were treated with liproxstatin-1 (selective ferroptosis inhibitor, 5mg/kg, daily i.p. postoperative days 1-7). Aortic diameter was measured on postoperative day 14 using video micrometry prior to harvest. Aortic tissue was analyzed for cytokine expression and histology. Hallmarks of ferroptosis such as lipid peroxidation (MDA) and glutathione (GSH) were measured in aortic tissue extracts. Statistical analysis was performed by ANOVA and p<0.05 was considered as statistically significant. Results: A significant increase in aortic diameter was observed in elastase-treated mice compared to controls on day 14 (155.5±8.7 vs. 1.9±3.3%; n=8-10/group; p<0.0001). A reduction in aortic diameter was observed in liproxstatin-1 treated mice compared to elastase treated mice (62.8±14 vs. 155.5±8.7%; n=8-10/group; p=0.0048). MDA and GSH levels in the aortic tissue were significantly decreased in liproxstatin-1 treated mice compared to elastase-treated mice alone (0.11±0.04 vs. 0.75±.1 nmol/mg; n=5-8/group; p<0.001; and 12.1±1.2 vs. 4.7±.0.7 μg/mg; n=5-8/group; p=0.04) . A decrease in immune cell (neutrophils and macrophages) infiltration, preservation of aortic morphology (increase in smooth muscle α-actin and decrease in elastin breaks) and decreased pro-inflammatory cytokine expression (IL-17, IL-1β, IL-6, MCP-1) was observed in liproxstatin-1-treated mice compared to elastase-treated mice alone by histological analysis. Conclusions: AAA formation is characterized by hallmarks of ferroptosis and pharmacological inhibition of ferroptosis attenuates aortic inflammation, vascular remodeling, and AAA formation. Ongoing studies will delineate the cell-specific roles of ferroptosis in progressive AAA formation and aortic rupture.