GSK2593074A Blocks Progression of Existing Abdominal Aortic Dilation

Abstract Objective Receptor interacting proteins kinase 1 and 3 (RIPK1 and RIPK3) have been shown to play essential roles in the pathogenesis of abdominal aortic aneurysms (AAAs) by mediating necroptosis and inflammation. We previously discovered a small molecular inhibitor GSK2593074A (GSK’074) that binds to both RIPK1 and RIPK3 with high affinity and prevents AAA formation in mice. In this study, we evaluated whether GSK’074 can attenuate progression of existing AAA in the calcium phosphate model. Methods C57BL6/J mice were subjected to the calcium phosphate model of aortic aneurysm generation. Mice were treated with either GSK’074 (4.65 mg/kg/day) or DMSO-controls starting 7 days after aneurysm induction. Aneurysm growth was monitored via ultrasound imaging every 7 days until harvest on day 28. Harvested aortas were examined via immunohistochemistry. The impact of GSK’074 on vascular smooth muscle cells and macrophages were evaluated via flow cytometry and transwell migration assay. Results At the onset of treatment, mice in both control (DMSO) and GSK’074 groups showed similar degree of aneurysmal expansion. The weekly ultrasound imaging showed a steady aneurysm growth in DMSO-treated mice. The aneurysm growth was attenuated by GSK’074 treatment. At euthanization, GSK’074-treated mice had significantly reduced progression in aortic diameter from baseline as compared to the DMSO-treated mice (83.2% SEM + 13.1% versus 157.2% SEM + 32.0%, P Conclusion GSK’074 is able to attenuate aneurysm progression in the calcium phosphate model. The ability to inhibit both vascular smooth muscle cell necroptosis and macrophage migration makes GSK’074 an attractive drug candidate for pharmaceutical treatment of aortic aneurysms.