Abstract 106: Receptor Interacting Kinase 1 Contributes to Pathogenesis of Abdominal Aortic Aneurysm by Causing Smooth Muscle Cell Necroptosis as Well as Inflammation

Abstract

Objectives: Abdominal aortic aneurysm (AAA), the progressive weakening and dilatation most commonly occurred in the infrarenal segment of aorta, is a common aortic disease associated with high lethality. Currently, there is no approved pharmacological treatment to effectively slow aneurysm growth or prevent rupture. We have recently demonstrated that inhibition of receptor interacting protein kinase 1 (RIP1), a critical mediator of necroptosis and apoptosis, attenuates aneurysm pathogenesis in a mouse elastase AAA model. Here, we tested whether RIP1 is also required for aneurysm formation in hypercholesterolemia mice stressed with Angiotensin II (AngII). Methods: Apolipoprotein E-deficient mice were infused with 1000 ng/kg/min of AngII for 28 days. The RIP1 inhibitor Necrostatin-1s (Nec-1s, 1.6 mg/kg/day) was administered via daily intraperitoneal (IP) injection. An aneurysm is defined as aortic expansion in the suprarenal ≥50% over infrarenal diameter. Results: The incidence of aneurysm formation was significantly lower in Nec-1s treated group compared to the DMSO group (33.35 vs 90.5%). Additionally, Nec-1s reduced aortic expansion (DMSO: 55.40±13.80%, Nec-1s: 121.1±16.44%, p<0.05 unpaired student’s t test). The number of mice that died prior to 28 days (due to aortic rupture) were comparable between DMSO and Nec-1 groups. Histological analysis showed preserved elastin fibers in aortae from Nec-1s treatment vs DMSO treatment. Immunohistochemical and immunofluorescence staining revealed that Nec-1s decreased the abundance of CD68+ cells as well as CD3+ T-cells but relative higher number of CD206 positive M2 macrophages in the aneurysm prone aortae. In vitro, Nec-1s attenuated smooth muscle necroptosis but stimulated biosynthesis of elastin. Furthermore, Nec-1s inhibited chemotaxis of monocytes/macrophages. Conclusions: Our data demonstrate that RIP1 contributes to aneurysm pathophysiology through regulation of cell death and inflammation infiltration. Being a small chemical molecule that is highly selective for RIP1, Necrostatin-1s may serve as a suitable drug treatment for AAAs.