Abstract 363: Irf8 And Securinine: Seeking Treatments For Abdominal Aortic Aneurysm

Objective: Abdominal aortic aneurysm (AAA) is defined as local weakening and dilatation of the abdominal aorta ≥50% and has high incidence in elderly. Current therapy is limited to surgical repair, only, no pharmacological therapy has shown effectiveness against AAA development and growth. Untreated AAA rupture is highly associated with death, and aged patients are at augmented risk for surgical complications. We therefore sought to identify novel agents that could be employed for medical AAA therapy. Methods: Using whole genome DNA methylation analysis (RRBS-Seq) in a transgenerational model of murine AAA, combined with transcriptional analysis of murine AAA tissue, we identified interferon regulatory factors (IRFs: a group of immune-system-related transcription factors (TF)), as major drivers of AAA risk and pathophysiology. We performed TF enrichment analysis that specifically suggested IRF8 as being crucial for AAA development. Drug Signatures Database (DSigDB) and Connectivity Map (CMap) analysis identified securinine, an alkaloid and traditional Chinese herbal medicine derived from Securinega suffruticosa , as a probable IRF8 inhibitor. Its vascular effects are relatively unknown. Results: We studied the effects of securinine using the porcine pancreatic elastase (PPE) model of AAA. Sonographic imaging data of 28-day securinine-treated mice (15 mg/kg) showed smaller aneurysm diameters and significantly downregulated gene expression of IRF8 and IFN-γ compared to control PPE groups. Conclusion: These data suggest that securinine may have therapeutic benefits on AAA development, potentially through regulation of IRF8.