SB290157, a selective complement C3a receptor antagonist, ameliorates aortic dissection by suppressing inflammatory signaling pathways to attenuate aortic wall inflammation and structural damage.

Abstract

PURPOSE: Aortic dissection (AD) is a life-threatening cardiovascular disease characterized by high mortality and a lack of effective pharmacotherapies. C3a, a complement C3 cleavage product, is critical for immunity, and co-inhibition of C3a and C5a prevents aortic aneurysm. However, whether and how single C3a activity inhibition alleviates AD remains unclear. METHODS: Levels of C3a, IL-6, C3 and NF-κB levels were compared between aortic samples from healthy individuals and AD patients. SB290157 (a C3aR antagonist) was administered to BAPN/Ang II-induced AD mice, where aortic lesions, survival, signaling pathways, cytokines and T lymphocyte subsets were assessed. Functional assays and phenotypic characterization were performed in MOVAS cells, and molecular docking and molecular dynamics simulations were conducted to analyze SB290157-C3aR interactions. RESULTS: AD patients exhibited significantly elevated C3a, IL-6, C3, and NF-κB levels, with male gender and hypertension identified as clinical risk factors for AD. The elevated cytokine and complement levels were recapitulated in mice. SB290157 alleviated aortic injury, improved survival, reduced pro-inflammatory factors, inhibited TLR4/NF-κB signaling, modulated T subsets, and preserved vascular smooth muscle integrity. In MOVAS cells, it suppressed inflammation, migration, and the synthetic phenotype, induced moderate dose-dependent apoptosis, and bound strongly to C3aR (8ZWF structure) with optimal binding parameters. CONCLUSION: SB290157 exerts anti-AD effects likely by modulating the C3a/C3aR axis, thereby mitigating C3a-mediated immunoinflammation and preserving the contractile phenotype of aortic smooth muscle cells. However, high-dose SB290157 (above 50 nM) may induce non-selective apoptosis in MOVAS cells, representing potential risks for therapeutic application.