Senkyunolide I inhibits abdominal aortic aneurysm via PARP-1-targeted restraint of large peritoneal macrophage migration.

Abstract

BACKGROUND: Abdominal aortic aneurysm (AAA) is a prevalent and potentially fatal cardiovascular disease, yet the precise therapeutic mechanism of the bioactive compound Senkyunolide I (SEI) against AAA is not fully understood. METHODS: Utilizing an elastase/BAPN-induced AAA mouse model, this study employed integrated network pharmacology, proteomics (LiP-MS), and biophysical validation (molecular docking, MST) to identify and confirm PARP-1 as a direct target of SEI. The therapeutic effect of SEI was evaluated in vivo by monitoring aortic dilation and histopathology, and its inhibitory effect on TNF-α-induced macrophage migration was assessed in vitro. The functional role of the SEI-PARP-1 axis was further verified using PARP-1 inhibitors and macrophage-targeted PARP-1 overexpression. RESULTS: In the elastase/BAPN-induced AAA model, which mimics human AAA progression and rupture risk, SEI treatment attenuated disease progression by reducing aortic dilation, collagen deposition, and elastin degradation. SEI directly bound to and downregulated PARP-1 expression in both AAA tissues and large peritoneal macrophages (LPMs). It dose-dependently suppressed TNF-α-induced LPMs migration in vitro and restored the AAA-induced reduction in peritoneal LPMs proportion in vivo, an effect also seen with pharmacological PARP-1 inhibition. In contrast, macrophage-specific PARP-1 overexpression abolished SEI's protection and promoted LPMs migration into aortic lesions. CONCLUSION: This study demonstrates that SEI attenuates AAA progression by targeting PARP-1 and inhibiting the migration of LPMs from the peritoneal cavity to the aortic lesion. These findings elucidate a novel pharmacological mechanism of SEI and underscore PARP-1 as a promising therapeutic target for AAA.