Abstract 677: Inhibition of Receptor-interacting Protein Kinase 1 With Necrostatin-1 and -1s Ameliorates Aneurysm Progression in the Elastase-induced Mouse Model of Abdominal Aortic Aneurysms (AAAs)

Objective: Abdominal aortic aneurysm (AAA) is a common vascular disease with a progressive nature. Currently, no pharmacological treatment is approved to effectively slow aneurysm growth or prevent rupture. We have recently demonstrated that receptor interacting protein kinase 3 (RIP3), a critical mediator of necroptosis, contributes to smooth muscle depletion and vascular inflammation associated with AAA. In this study, we tested the hypothesis that inhibition of necroptosis may mitigate aneurysm progression using Necrostatin-1 (Nec-1) or an optimized form of Nec-1 called Nec-1s (7-Cl-O-Nec-1), known inhibitors of another necroptosis mediator RIP1. Approach and Results: Using elastase perfusion model, we first demonstrated that Nec-1 attenuated aneurysm formation when administered daily by intraperitoneal (IP) injection started 30 min before aneurysm induction. Nec-1 also profoundly reduced elastin fragmentation, macrophage infiltration and SMC necrosis after elastase perfusion. To test whether RIP1 inhi...